Improving the health of school-aged children can yield substantial benefits for cognitive development and educational achievement. However, there is limited experimental evidence of the benefits of alternative school-based malaria interventions or how the impacts of interventions vary according to intensity of malaria transmission. We investigated the effect of intermittent screening and treatment (IST) for malaria on the health and education of school children in an area of low to moderate malaria transmission. A cluster randomised trial was implemented with 5,233 children in 101 government primary schools on the south coast of Kenya in 2010–2012. The intervention was delivered to children randomly selected from classes 1 and 5 who were followed up for 24 months. Once a school term, children were screened by public health workers using malaria rapid diagnostic tests (RDTs), and children (with or without malaria symptoms) found to be RDT-positive were treated with a six dose regimen of artemether-lumefantrine (AL). Given the nature of the intervention, the trial was not blinded. The primary outcomes were anaemia and sustained attention. Secondary outcomes were malaria parasitaemia and educational achievement. Data were analysed on an intention-to-treat basis. During the intervention period, an average of 88.3% children in intervention schools were screened at each round, of whom 17.5% were RDT-positive. 80.3% of children in the control and 80.2% in the intervention group were followed-up at 24 months. No impact of the malaria IST intervention was observed for prevalence of anaemia at either 12 or 24 months (adjusted risk ratio [Adj.RR]: 1.03, 95% CI 0.93–1.13, p = 0.621 and Adj.RR: 1.00, 95% CI 0.90–1.11, p = 0.953) respectively, or on prevalence of P. falciparum infection or scores of classroom attention. No effect of IST was observed on educational achievement in the older class, but an apparent negative effect was seen on spelling scores in the younger class at 9 and 24 months and on arithmetic scores at 24 months. In this setting in Kenya, IST as implemented in this study is not effective in improving the health or education of school children. Possible reasons for the absence of an impact are the marked geographical heterogeneity in transmission, the rapid rate of reinfection following AL treatment, the variable reliability of RDTs, and the relative contribution of malaria to the aetiology of anaemia in this setting. www.ClinicalTrials.gov NCT00878007 Please see later in the article for the Editors' Summary Every year, more than 200 million cases of malaria occur worldwide and more than 600,000 people, mostly children living in sub-Saharan Africa, die from this mosquito-borne parasitic infection. Malaria can be prevented by controlling the night-biting mosquitoes that transmit Plasmodium parasites and by sleeping under insecticide-treated nets to avoid mosquito bites. Infection with malaria parasites causes recurring flu-like symptoms and needs to be treated promptly with antimalarial drugs to prevent the development of anaemia (a reduction in red blood cell numbers) and potentially fatal damage to the brain and other organs. Treatment also reduces malaria transmission. In 1998, the World Health Organization and several other international bodies established the Roll Back Malaria Partnership to provide a coordinated global approach to fighting malaria. In 2008, the Partnership launched its Global Malaria Action Plan, which aims to control malaria to reduce the current burden, to eliminate malaria over time country by country, and, ultimately, to eradicate malaria. In recent years, many malaria-endemic countries (countries where malaria is always present) have implemented successful malaria control programs and reduced malaria transmission levels. In these countries, immunity to malaria is now acquired more slowly than in the past, the burden of clinical malaria is shifting from very young children to older children, and infection rates with malaria parasites are now highest among school-aged children. Chronic untreated Plasmodium infection, even when it does not cause symptoms, can negatively affect children's health, cognitive development (the acquisition of thinking skills), and educational achievement. However, little is known about how school-based malaria interventions affect the health of children or their educational outcomes. In this cluster randomized trial, the researchers investigate the effect of intermittent screening and treatment (IST) of malaria on the health and education of school children in a rural area of southern Kenya with low-to-moderate malaria transmission. Cluster randomized trials compare the outcomes of groups (“clusters”) of people randomly assigned to receive alternative interventions. IST of malaria involves periodical screening of individuals for Plasmodium infection followed by treatment of everyone who is infected, including people without symptoms, with antimalarial drugs. The researchers enrolled more than 5,000 children aged between 5 and 20 years from 101 government primary schools in Kenya into their 24-month study. Half the schools were randomly selected to receive the IST intervention (screening once a school term for infection with a malaria parasite with a rapid diagnostic test [RDT] and treatment of all RDT-positive children, with or without malaria symptoms, with six doses of artemether-lumefantrine), which was delivered to randomly selected children from classes 1 and 5 (which contained younger and older children, respectively). During the study, 17.5% of the children in the intervention schools were RDT-positive at screening on average. The prevalences of anaemia and parasitemia (the proportion of children with anaemia and the proportion who were RDT-positive, respectively) were similar in the intervention and control groups at the 12-month and 24-month follow-up and there was no difference between the two groups in classroom attention scores at the 9-month and 24-month follow-up. The IST intervention also had no effect on educational achievement in the older class but, unexpectedly, appeared to have a negative effect on spelling and arithmetic scores in the younger class. These findings indicate that, in this setting in Kenya, IST as implemented in this study provided no health or education benefits to school children. The finding that the educational achievement of younger children was lower in the intervention group than in the control group may be a chance finding or may indicate that apprehension about the finger prick needed to take blood for the RDT had a negative effect on the performance of younger children during educational tests. The researchers suggest that their failure to demonstrate that the school-based IST intervention they tested had any long-lasting health or education benefits may be because, in a low-to-moderate malaria transmission setting, most of the children screened did not require treatment and those who did lived in focal high transmission regions, where rapid re-infection occurred between screening rounds. Importantly, however, these findings suggest that school screening using RDT could be an efficient way to identify transmission hotspots in communities that should be targeted for malaria control interventions. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001594.