In the present work, we analyze the recognition of synthetic polypeptides encompassing the aminoterminal (amino acids 22-125) and the carboxy terminal (289-390) regions of the circumsporozoite (CS) protein of Plasmodium falciparum by sera from donors living in endemic area of South America and Africa. Two populations were studied: one on the Colombian Pacific coast, with low endemicity for malaria; and a western African village exposed to a very intense transmission of P. falciparum. Antibodies directed to the two polypeptides were found at high titers in both populations. Furthermore, this response was observed in individuals lacking antibodies to the highly repetitive central sequence of the CS protein (NANP). The epitopes responsible for this recognition were mapped to the region 81-125 and 316-346 of the N- and C-termini, respectively. When the two populations were compared, both showed high titers of antibodies to the two flanking peptides. However, while 95% of the sera from African adults showed antibodies against the repeat region of the CS protein, only 37% of the Colombian adults studied had these antibodies. Furthermore, African donors of various ages exhibited different patterns of recognition of the two polypeptides. In African children less than five years of age, antibodies were found in comparable levels to Colombian adults; however, in older African donors, the response to NANP became dominant. These findings may reflect the skewing effect of the humoral response towards the central repetitive epitope under conditions of frequent exposure to malaria infections. The production of such polypeptides encompassing regions that contain multiple epitopes for antibodies, T helper, and cytotoxic T lymphocyte epitopes would be advantageous in the generation of new and more efficient malaria vaccines.