Children with symptomatic malaria in Bissau, Guinea-Bissau were randomly assigned to treatment with a 25 mg/kg total dose of chloroquine as recommended by the National Malaria Program or with a higher total dose of 50 mg/kg. Sixty-seven and 62 children, respectively, completed the treatment and were then followed once a week for five weeks. Treatment with a dose of 50 mg/kg was significantly more effective than treatment with 25 mg/kg in preventing recrudescence. The cumulative relative risk (95% confidence interval) of having parasitemia in the low-dose group during follow-up was 0.20 (0.08-0.52) on day 21, 0.38 (0.17-0.86) on day 28, and 0.48 (0.23-0.98) on day 35. Few adverse events were reported, although more children complained of vomiting and diarrhea on day 2 in the high-dose group compared with those in the low-dose group. However, this difference was not statistically significant. We conclude that a dose of 50 mg/kg of chloroquine could be recommended for treatment of Plasmodium falciparum malaria in Bissau. To minimize the risk of side effects, this higher dose should be given divided into two daily doses over a three-day period.