This study examines the effect of different levels of fetal hemoglobin (Hb F) and the presence or absence of genes for alpha-thalassemia on the red cell indices and degree of anemia among 102 patients with homozygous sickle cell disease (S/S) between the ages of 15 and 62 years. Patients were divided into those with an average Hb F of less than 10 gm/L ("low" Hb F group) and those with greater than 10 gm/L ("high" Hb F group). alpha-Thalassemia was assessed by restriction enzyme analysis of DNA by the Southern blotting technique. Homozygosity for the beta(s) gene was confirmed by restriction enzyme analysis of DNA using the enzyme Mst II. There were 51 patients with four alpha-globin genes, 28 of whom had "high" and 23 "low" Hb F levels. Fifty-one patients had alpha-thalassemia, 38 of whom were heterozygous and 13 homozygous for the 3.7 kb alpha-thalassemia deletion. Nine had "high" and 31 had "low" Hb F. Irrespective of alpha-globin genotype, patients in the high Hb F group had a higher mean Hb, Hct, MCV, and MCH than those in the low HB F group. In patients without alpha-thalassemia Hb F was positively correlated with MCV and MCH (p less than 0.001), patients with high Hb F levels having macrocytosis confirmed by microhematocrit studies. Patients with alpha-thalassemia had a lower MCHC than patients with four alpha-globin genes and this was not significantly affected by the level of Hb F. The combination of alpha-thalassemia and high levels of Hb F appears to result in a distinctive S/S phenotype that is similar to the type of S/S disease described in Southern India.