During the intracellular development of the human malarial parasite, Plasmodium falciparum, cryptic regions of the erythrocyte band 3 protein are exposed. Antibodies against these band 3-related neoantigens block cytoadherence, and peptides based on amino acid sequences of putative exofacial loops of band 3 protein block the in vitro and in vivo adherence of P. falciparum-infected erythrocytes. At present, it is not known whether reactivity to these antigens is related to exposure to the malaria parasite or is correlated with protective immunity. The reactivities of plasma to peptides containing amino acid sequences of putative exofacial loops 3 and 7 of human band 3 protein were determined for children and adults living in an area of perennial malaria transmission (Liberia) and for donors who had never been exposed to malaria (Denmark). Plasma samples from children and adults living in an area of intense malaria transmission showed a much higher reactivity with the band 3 peptides than did those from nonimmune individuals. High reactivity to the loop 3 peptide (amino acids 546 to 555) was correlated with lower mean parasite density in children in the 5- to 9-year-old age group. The presence of antibodies against loop 3 and 7 peptides was not associated with a low packed erythrocyte volume (hematocrit); in fact, higher-than-average reactivities to both peptides were positively correlated with high hematocrit values, indicating that antibodies which specifically recognize the band 3-related neoantigens are not involved in hemolysis (autoimmunity).