Reports that Trimethoprim® plus Sulfalene® are an effective cure for Plasmodium falciparum malaria in man suggested a laboratory study of these drugs to aid in evaluating tests with animals in the search for new antimalarials. Rhesus monkeys with trophozoite-induced P. knowlesi infections were treated with Trimethoprim and Sulfalene, alone or in combination, and followed clinically for 65 days. The infection was lethal for all untreated animals within 5 to 7 days after inoculation. Seven daily oral doses of 100 mg per kilogram of body weight (mpk) of Trimethoprim or 0.5 mpk of Sulfalene were effective in curing P. knowlesi, clearing parasitemia within 3 to 4 days. Single doses of 25 mpk Trimethoprim or 0.5 mpk Sulfalene alone were not curative; but as a combined treatment, these drug levels cured all animals, clearing parasitemia in an average of 4.6 days. The antimalarial efficacy of Trimethoprim and Sulfalene against P. knowlesi infection appear to be at least additive. These results parallel the findings in the radical cure of falciparum malaria in man and support the continued use of simian models in the search for new antimalarials.