Sulfalene and trimethoprim were used individually and in association in the treatment of nonimmune or slightly immune adult patients infected with falciparum malaria caused by six strains of parasite, some of which were resistant and some sensitive to chloroquine, pyrimethamine, and chlorguanide. Doses of 0.25 gram or 1.0 gram of sulfalene were administered to 33 patients, 14 of whom, all infected with pyrimethamine-resistant strains, were not cured. Trimethoprim, in a course of 1.5 gram daily for 7 days, cured 5 of 10 patients. The two drugs together produced a variable response when given for 2 days or less; a 3-day course consisting of sulfalene 1.0 gram and trimethoprim 1.5 gram daily (in divided doses) cured 10 of 14 patients, but the parasitemia in 2 patients who were not cured was not cleared even temporarily by the treatment. These 2 patients were not cured when they received 5-day courses at the same daily dosage, assay of plasma levels confirming absorption of the trimethoprim component. Patients whose infections had broken through prophylaxis by the sulfone di-formyl-DDS were unlikely to be cured by sulfalene and trimethoprim, but their parasites when transferred to other people proved sensitive to these drugs. Alternative explanations are proposed: 1) in some persons, unidentified host factors interfere with the action of the absorbed drug upon a sensitive parasite; 2) the parasite develops some degree of drug resistance in certain hosts but loses it upon transfer to other hosts.