Adults claiming resistance to malaria were identified in the Sennar region of central Sudan, where P. falciparum is hyperendemic but seasonal in transmission. Indirect fluorescent antibody (IFA) titers of sera from these individuals were comparable to those of malaria patients with positive blood films, indicating equal exposure, while in vitro antiparasitic activity of their sera tended to be higher, indicating an effective immunological response to falciparum malaria. Hemoglobin S (Hb S) was significantly more prevalent in adults resistant to malaria. This trait offers protection at the erythrocyte level and it is also possible that it could enhance the ability of carrier adults to acquire protective immunity. Erythrocyte 6-phosphogluconate dehydrogenase A (PGDA) and phosphoglucomutase 1 (PGM1), phenotypes of unknown relevance to protection against falciparum malaria, were also significantly more prevalent in those claiming resistance to malaria. A trend of higher prevalence for erythrocyte glucose-6-phosphate dehydrogenase deficiency (G6PD-), Kell (+) and transferrin D (TfD) was detected among resistant individuals and higher KP(a+) and P2 among malaria patients, but the numbers evaluated in this study did not allow determination of statistical significance. No association was found with erythrocyte glyoxalases, ABO and Duffy blood groups and serum haptoglobins.