The prophylactic efficacy of antimalarial drugs was studied in nonimmune adult male volunteers challenged by mosquitoes infected with two chloroquine-resistant strains of Plasmodium falciparum from Vietnam. Chloroquine, 300 mg (base), with primaquine, 45 mg (base), given at weekly intervals for 8 weeks from the time of challenge, protected two of four men from the Vietnam (Smith) strain. Chlorguanide (proguanil), 200 mg daily, did not protect against the Smith strain. Pyrimethamine, 25 mg weekly, was ineffective against the Smith strain, but suppressed the Vietnam (Brai.) strain. Sulfalene, 200 or 250 mg weekly, with chloroquine and primaquine suppressed both these strains. Diformyl diaminodiphenyl sulfone (DFD), 100 to 800 mg each week, with chloroquine and primaquine prevented the development of Smith-strain malaria in 41 of 45 men and of Brai.-strain malaria in 9 men; 800 mg weekly with chloroquine protected an individual challenged with the Smith strain. Primaquine was an effective gametocytocide and sporontocide in Smith and Brai.-strain malaria, while pyrimethamine interfered with oocyst development of the Brai. but not of the Smith strain.