Malaria infections in Africa frequently include multiple parasite strains. We examined the relationship between the number of infecting Plasmodium falciparum strains and the responses to 3 different combination therapies in 3072 patients with uncomplicated malaria at 7 sites in Uganda. Patients infected with > or =3 strains had almost 3 times the odds of treatment failure (odds ratio, 2.93 [95% confidence interval, 2.51-3.43]; P<.001), compared with those infected with 1 or 2 strains. Our data suggest that efforts to reduce the complexity of infection in highly endemic areas through the use of intermittent presumptive therapy, improved case management, and reduction in transmission intensity may improve the efficacy of antimalarial therapies.