OBJECTIVE: To assess the safety of chloroquine (CQ) as prophylaxis against Plasmodium vivax infection during pregnancy. METHOD: One thousand pregnant Karen women were enrolled in a randomized, double-blind, placebo-controlled trial of chemoprophylaxis with chloroquine (500 mg phosphate (or 300 mg base) weekly). Women received a median (range) chloroquine phosphate total dose of 9500 (1500-17 500) mg. The mothers were actively followed from inclusion to delivery and their infants until 12 months of age. RESULTS: Chloroquine prophylaxis completely prevented P. vivax episodes; 10.1% (95%CI: 7.3-14.5) of women in the placebo group experienced at least one episode of vivax malaria but no episode occurred in women in the CQ group. By contrast, the numbers of P. falciparum episodes were similar in each group: 7.4% (95%CI: 3.7-11.1) and 5.6% (95%CI: 3.3-7.9) in the placebo and CQ groups respectively (P = 0.56). Chloroquine prophylaxis was well tolerated and there was no difference in the proportions of reported side effects between CQ treated and placebo groups except for the duration of palpitations and sleeping disorders which were more frequent in those who had received CQ. Chloroquine prophylaxis had no impact on maternal anaemia, birth weight, gestational age, development of newborns or on growth, neurological development or visual acuity in infants at 1 year of age. CONCLUSION: Chloroquine is safe and effective as prophylaxis against P. vivax during pregnancy in this population.