BACKGROUND: Pediatric diarrhea can be caused by a wide variety of pathogens, from bacteria to viruses to protozoa. Pathogen prevalence is often described as seasonal, peaking annually and associated with specific weather conditions. Although many studies have described the seasonality of diarrheal disease, these studies have occurred predominantly in temperate regions. In tropical and resource-constrained settings, where nearly all diarrhea-associated mortality occurs, the seasonality of many diarrheal pathogens has not been well characterized. As a retrospective study, we analyze the seasonal prevalence of diarrheal pathogens among children with moderate-to-severe diarrhea (MSD) over three years from the seven sites of the Global Enteric Multicenter Study (GEMS), a case-control study. Using data from this expansive study on diarrheal disease, we characterize the seasonality of different pathogens, their association with site-specific weather patterns, and consistency across study sites. METHODOLOGY/PRINCIPAL FINDINGS: Using traditional methodologies from signal processing, we found that certain pathogens peaked at the same time every year, but not at all sites. We also found associations between pathogen prevalence and weather or "seasons," which are defined by applying modern machine-learning methodologies to site-specific weather data. In general, rotavirus was most prevalent during the drier "winter" months and out of phase with bacterial pathogens, which peaked during hotter and rainier times of year corresponding to "monsoon," "rainy," or "summer" seasons. CONCLUSIONS/SIGNIFICANCE: Identifying the seasonally-dependent prevalence for diarrheal pathogens helps characterize the local epidemiology and inform the clinical diagnosis of symptomatic children. Our multi-site, multi-continent study indicates a complex epidemiology of pathogens that does not reveal an easy generalization that is consistent across all sites. Instead, our study indicates the necessity of local data to characterizing the epidemiology of diarrheal disease. Recognition of the local associations between weather conditions and pathogen prevalence suggests transmission pathways and could inform control strategies in these settings.