Emphasis on retaining chloroquine as the first-line therapy for Plasmodium falciparum infections in most of sub-Saharan Africa for as long as it remains effective has resulted in widespread reliance on chloroquine in areas where it can have little effect on P. falciparum parasitemia. To address this issue, clinical, parasitologic, and hematologic responses to chloroquine or pyrimethamine/sulfadoxine treatment were assessed among very young children in Malawi (n = 153) and Kenya (n = 73). The median time to resumption of clinical symptoms in chloroquine-treated children was 13.5 days in Malawi and 9.5 days in Kenya. Children treated with pyrimethamine/sulfadoxine maintained clinical improvement and had greater increases in their hemoglobin concentration during the follow-up period than did children treated with chloroquine. Treatment with chloroquine failed to produce either a durable clinical improvement or optimal hematologic recovery. Consequently, chloroquine can no longer be considered adequately effective therapy of clinical P. falciparum malaria in very young children in these areas of Africa.