Specific regions of the human erythrocyte anion transport protein, AE 1 or band 3, have been identified as being adhesive in Plasmodium falciparum-infected-erythrocytes. In addition, synthetic peptides based on these sequences and murine monoclonal antibodies (Mabs) to these block cytoadherence/sequestration. These findings suggest the possibility that humans who are able to control P. falciparum infections may produce anti-adhesin (and thus anti-band 3) antibodies. To test this hypothesis, sera from individuals living in The Gambia and southern California were assayed for reactivity to decapeptides patterned on putative exofacial regions of the human anion transporter, band 3 protein. Sera from an area highly endemic for malaria, The Gambia, were found to have strong reactivity to well-defined regions of the band 3 protein (some of which contain the adhesin), whereas minimal reactivity was observed with sera from individuals living in a geographic area where malaria transmission is rare (California). Sera from The Gambia reacted strongly with residue blocks 534–560, 638–660, and 808–842. Gambian sera that reacted strongly with peptides patterned on band 3 failed to react with native band 3 on an immunoblot, but did react with fixed P. falciparum-infected erythrocytes. Using reactivity to decapeptides has allowed the determination of the epitopes of previously described murine MAbs that inhibit or promote cytoadherence; this reactivity with a specific region of a protein can be correlated with a specific effect on cytoadherence. A MAb (5H12) directed against amino acids 474–488 promoted cytoadherence, whereas those directed against amino acids 540–550 and 750–766 (Mabs 1C4 and 4A3, respectively) inhibited cytoadherence.