Plasmodium coatneyi produced ring-infected erythrocyte surface antigen (RESA) during infection of the rhesus monkey. This antigen was immunogenic and elicited an antibody response that was not persistent but was boosted by repeated infections in a manner similar to that seen in P. falciparum infections in humans. Preliminary data showed that the appearance and increasing titer of antibodies to P. coatneyi RESA-like antigen were associated with prolongation of intervals from inoculation to patency and with control of parasitemia. Studies using both immunofluorescence assay and Western blot analysis showed that P. coatneyi-immune rhesus serum cross-reacted with P. falciparum antigens, but P. falciparum immune human serum did not recognize P. coatneyi antigens in either assay. These results show that P. coatneyi expresses RESA-like antigen that elicits an antibody response similar to that observed for human antibody to P. falciparum RESA. However, antibodies to P. coatneyi did not cross-react with P. falciparum RESA in erythrocyte membrane immunofluorescence assay and dot immunoblot analysis, suggesting that different immunogenic epitopes are present on the two molecules. Our observations support the use of this primate model in RESA-based vaccine development.