We explored associations between Plasmodium falciparum drug resistance–mediating polymorphisms and clinical presentations in parasitemic children enrolled in a cross-sectional survey in Tororo, Uganda, using a retrospective case-control design. All 243 febrile children (cases) and 243 randomly selected asymptomatic children (controls) were included. In a multivariate analysis adjusting for age, complexity of infection, and parasite density, the prevalence of wild-type genotypes was significantly higher in febrile children compared to asymptomatic children ( pfcrt K76T: odds ratio [OR] 4.41 [95% confidence interval {CI}, 1.28–15.1]; pfmdr1 N86Y: OR 4.08 [95% CI, 2.01–8.31], and pfmdr1 D1246Y: OR 4.90 [95% CI, 1.52–15.8]), suggesting greater virulence for wild-type parasites. ; International Center of Excellence in Malaria Research grant and a Fogarty International Center training grant