(1) Malaria remains a significant health threat to military and civilian personnel de-ployed to endemic regions. Despite recommended chemoprophylaxis, compliance var-ies substantially, potentially impacting clinical outcomes when infections occur. This study investigated the relationship between antimalarial prophylaxis compliance and disease severity among United Nations peacekeepers and associated personnel in South Sudan. (2) Methods: A prospective observational study was conducted at the Vietnam Level 2 Field Hospital in Bentiu, South Sudan from 2018-2024, analyzing 258 confirmed malaria cases. Patients were stratified based on prophylactic medication adherence: a prophylaxis group (n=140, including both regular and irregular users) and a non-prophylaxis group (n=118). Clinical manifestations, laboratory parameters, parasite density, and disease severity were compared between groups. (3) Results: De-spite similar rates of atypical fever presentations between groups (65.0% vs. 55.9%, p=0.14), significant differences emerged in disease severity and laboratory parameters. Non-adherence to prophylaxis was associated with increased risk of anemia (OR=2.81, 95%CI 1.27-6.25, p< 0.01), severe thrombocytopenia (OR=3.76, 95%CI 2.24-6.31, p< 0.01), and elevated liver enzymes (AST: OR=2.26, 95%CI 1.36-3.75, p< 0.001; ALT: OR=1.86, 95%CI 1.13-3.05, p< 0.01). Most importantly, prophylactic abstention signifi-cantly increased risk for malaria with warning signs (OR=2.33, 95%CI 1.25-4.34, p< 0.01) and high parasite density (OR=3.07, 95%CI 1.81-5.20, p< 0.001). All patients achieved parasitological clearance by day three post-treatment. (4) Conclusions: While antimalarial prophylaxis did not prevent infection in our cohort, it significantly re-duced disease severity, parasitemia, and laboratory abnormalities when breakthrough infections occurred. These findings emphasize the importance of prophylactic com-pliance among non-immune individuals in high-transmission settings, even when per-fect adherence cannot be achieved.