A double-blind, placebo-controlled study of mefloquine antimalarial prophylaxis in pregnancy (> 20 weeks of gestation) was conducted in 339 Karen women living in an area of multidrug-resistant malaria transmission on the Thai-Burmese border. Mefloquine gave > or = 86% (95% confidence interval [CI], 59%-94%) protection against Plasmodium falciparum and complete protection against Plasmodium vivax infections. Mefloquine prophylaxis was well tolerated; use of an initial loading dose (10 mg/kg) was associated with transient dizziness, but there were no other significant adverse effects on the mother, the pregnancy, or infant survival or development (followed for 2 years). Falciparum malaria was associated with maternal anemia and a mean reduction in birth weight in gravidae I, II, and III of 225 g (95% CI, 26-423). Maternal anemia at delivery (hematocrit < 30%) was associated with increased infant mortality: 26% versus 15% (relative risk, 1.9; 95% CI, 1.1-3.2). Mefloquine is safe and effective for antimalarial prophylaxis in the second half of pregnancy.