The presence of chloroquine-resistant Plasmodium vivax malaria in the New World has been suspected but not confirmed. We report the cases of three patients who acquired vivax malaria in Guyana, South America, and for whom standard chloroquine therapy (25 mg/kg) failed despite therapeutic blood levels. The optimal treatment of chloroquine-resistant P. vivax malaria is unknown, but recent studies suggest that a combination of chloroquine (25 mg/kg) and high-dose primaquine (2.5 mg/kg over 48 hours) is effective therapy. Two of our patients had recurrences of P. vivax malaria 6-8 weeks after receiving directly observed therapy with this combination. These cases confirm the presence of chloroquine-resistant P. vivax in Guyana and emphasize the need for better treatment regimens for chloroquine-resistant and primaquine-resistant P. vivax malaria.