Two population groups from Western India with a high prevalence of the beta(S) gene, one tribal (Valsad) and the other nontribal (Nagpur), were studied. The beta(S) gene frequency in both populations was similar (0.22 vs. 0.23), but not the clinical expression of sickle-cell anemia (SS): the sickle homozygotes in the tribal group appeared to have a mild clinical course, whereas the majority in the nontribal group exhibited a more severe clinical phenotype. Both tribal and nontribal SS patients had a similarly high mean hemoglobin (Hb)F expression (18.5% vs. 15.5%) and a high number of F cells (72.3% vs. 66.6%). DNA analysis of the beta-globin gene cluster region revealed that in these two populations, this portion of DNA was identical with and corresponded to the typical Arab-Indian haplotype. Nevertheless, in heterozygotes, the mean beta(S) expression was lower (27.9%) in the tribal as compared to the nontribal group (35.5%). The major epistatic factor distinguishing the milder presentation in tribals vs. a more severe manifestation in nontribals was the very high frequency (0.97) of the alpha-thalassemia gene in the former as compared to the latter (0.24). We conclude that the phenotypic expression of sickle-cell anemia, linked to the Arab-India haplotype and expressing similar levels of HbF and F cells, is not uniformly mild in India and that alpha-thalassemia is a powerful and additional epistatic factor in the Indian subcontinent.