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This report describes, illustrates, and validates the major features of a procedure designed to provide primary assessments of the activities of potential antimalarial drugs against infections with chloroquine-resistant or pyrimethamine-resistant strains of Plasmodium falciparum in owl monkeys of Colombian origin. Studies with 14 specially selected compounds have shown that the test method has the capacity to identify and quantify diverse levels of therapeutic efficacy among agents that differ widely in chemical structure. Extended studies with two of the above compounds indicate that such assessments have an acceptable level of reproducibility. Experiments with two other agents, structurally different from those in the selected group, have shown that the impacts of pyrimethamine resistance (or chloroquine resistance) on the activity of a compound can be readily identified during routine application of the test procedure, as can emergence of parasites resistant to the test agent. The above body of information can usually be acquired in infections with two strains of P. falciparum, one chloroquine-resistant, the other pyrimethamine-resistant, with commitments of no more than 1.5 g of test compound and 12 owl monkeys. These modest requirements have made it possible to utilize human plasmodial infections in the owl monkey in the search for new blood schizonticidal drugs more broadly effective than those currently available.