A case-control study was conducted to evaluate the efficacy of the combination of chloroquine plus proguanil as malaria prophylaxis in a non-immune population living in the Central African Republic. Cases were patients presenting with a malaria attack confirmed by a positive blood film and/or an HRP2 positive antigen test at the Pasteur Institute of Bangui. Two control subjects were included per case: one was a relative or close friend and the other was matched to the patient with respect to the length of stay. A questionnaire assessing malaria prophylaxis habits and malarial risk factors over the 2-month period prior to inclusion in the study was given to 48 cases and 96 controls. A conditional logistic regression was used to identify risk factors. The efficacy of the chloroquine plus proguanil regimen was found to be high (95.5%, 95% CI 74.0-99.2%) in this country known for high chloroquine resistance. Our data lend some support to the use of chloroquine plus proguanil in Bangui, and the protective efficacy of chloroquine plus proguanil should now be studied prospectively as part of a randomised controlled trial of various prophylactic drugs.