The epidemiology of Helicobacter pylori infection has changed with improvements in sanitation and methods of eradication. We performed a systematic review and meta-analysis to evaluate changes in the global prevalence of H pylori infection. We performed a systematic search of the MEDLINE and EMBASE databases for studies of the prevalence of H pylori infection published from January 1, 1970 through January 1, 2016. We analyzed data based on United Nations geoscheme regions and individual countries. We used a random effects model to calculate pooled prevalence estimates with 95% confidence intervals (CIs), weighted by study size. We extrapolated 2015 prevalence estimates to obtain the estimated number of individuals with H pylori infection. Among 14,006 reports screened, we identified 263 full-text articles on the prevalence of H pylori infection; 184 were included in the final analysis, comprising data from 62 countries. Africa had the highest pooled prevalence of H pylori infection (70.1%; 95% CI, 62.6−77.7), whereas Oceania had the lowest prevalence (24.4%; 95% CI, 18.5−30.4). Among individual countries, the prevalence of H pylori infection varied from as low as 18.9% in Switzerland (95% CI, 13.1−24.7) to 87.7% in Nigeria (95% CI, 83.1−92.2). Based on regional prevalence estimates, there were approximately 4.4 billion individuals with H pylori infection worldwide in 2015. In a systematic review and meta-analysis to assess the prevalence of H pylori infection worldwide, we observed large amounts of variation among regions—more than half the world’s population is infected. These data can be used in development of customized strategies for the global eradication.