We studied the effects of daily proguanil compared to weekly chloroquine as malaria prophylaxis in 170 children living in a malaria-endemic area along the Thai-Burmese border. Children aged 5–10 years were matched for age, weight, and presence of splenomegaly then randomly assigned to receive either proguanil (equivalent of 200 mg daily adult dose) or chloroquine (equivalent of 300 mg base weekly). All medications were administered by the investigators and malaria smears were performed on a weekly basis. Among 85 children taking proguanil for 524 human-weeks, there were 17 cases of falciparum malaria and 11 cases of vivax. Of 85 children on chloroquine for 537 human-weeks, there were 24 cases of falciparum and 1 case of vivax. There were no statistically significant differences between the two regimens when analyzed either as suppressive or as causal Plasmodium falciparum prophylactics. The data were suggestive that proguanil may have some causal prophylactic effect against falciparum malaria. There were significantly more vivax prophylactic failures (P < 0.01) in the proguanil group. Side effects were infrequent, mild, and comparable in both groups.