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Antimalarial drug treatment policy in sub-Saharan Africa is generally guided by the results of clinical drug efficacy studies in patients with uncomplicated Plasmodium falciparum malaria. The selection criteria used to enroll these patients often vary and may have a significant impact on treatment outcomes. In Kampala, Uganda, we investigated the impact of age, baseline temperature, and pre-treatment parasite density on estimates of treatment efficacy using a statistical modeling approach in 2,138 patients enrolled in six clinical trials involving seven different treatment regimens. Decreasing age, increasing temperature, and increasing parasite density were all independent predictors of an increased risk of treatment failure across all treatment groups. Compared with an unrestrictive approach to subject selection, enrolling only patients fulfilling selection criteria recommended by the World Health Organization (age < 5 years old, documented fever, and parasite density < 200,000/μL) increased the risk of treatment failure by 25–60% for the different treatment regimens. Caution should be taken when comparing results from drug efficacy studies with different subject selection criteria.