The ring-infected erythrocyte surface antigen (RESA), a Plasmodium falciparum merozoite antigen, is a major vaccine candidate against falciparum malaria. To investigate the protective role of antibodies to RESA and its 4-mer, 8-mer, and 11-mer repeated amino acid sequences under conditions of natural exposure, a case-control and a cohort study were carried out in 1988 in a rural community in Madagascar where malaria reappeared recently. Fifty cases with greater than 1,000 P. falciparum per microliter of blood, and 45 controls with a negative blood smear were enrolled and sera were collected. Forty-one controls were followed for 20 weeks to identify malarial attacks. Protection against clinical malaria was assessed by the absence of malarial attacks requiring therapy. At enrollment, positivity rates and reactivity levels to RESA or repeats were similar in cases and controls. The 11-mer repeat antibody level was higher in the 26 controls who experienced at least one malarial attack during follow-up than in the 15 other controls (p less than 0.01). Thus, antibodies to the 11-mer repeat were predictors of the subsequent appearance of the disease. After adjustment for antibodies to the 11-mer repeat, antibodies to whole RESA had a negative predictive value on the occurrence of malarial attacks (p = 0.04). Different epitopes within the RESA molecule may elicit production of antibodies with different activities.