OBJECTIVE To study the issues and dilemmas in prenatal diagnosis of Sickle cell anemia (SCA) and to evaluate the role of genetic modifiers in counseling the families. METHODS The authors studied the genotype in 47 individuals with increased HbS and three representative families were taken as an example for describing various issues which need to be sorted out for appropriate counseling. RESULTS Of 47 individuals 24 were S beta thalassemia, 14 were homozygous sickle cell anemia (SS) and 9 were HbS trait. In the S beta thalassemia and homozygous SS cases, anemia was presenting manifestation in all. The transfusion requirement in these varied from 0-12 transfusions/ year. Hepatosplenomegaly was seen in 27 cases (71%) and only splenomegaly in 9 cases (23.7%). Jaundice was observed in 34 cases (84.2%). All the 47 subjects (including HbS trait) were studied by Hb Variant system and underwent DNA analysis for beta globin gene mutations, alpha globin gene number and XmnI polymorphism. One or two alpha gene deletion of 3.7 kb (-α3.7/αα or -α3.7/-α3.7) was found in 11 out of 47 cases whereas alpha triplication was found in 2 cases. 28 cases were heterozygous (+/-) for XmnI polymorphism, 9 were homozygous negative (-/-) and 10 were homozygous positive (+/+). Patients with SCA co-inherited with α-thalassemia have less hemolysis as revealed by lower reticulocyte counts than with normal alpha genotype. The authors further discuss the issues and dilemmas faced during prenatal counseling of three families during this study. CONCLUSIONS The knowledge of the relationship between genotype and phenotype, effect of the modifier genes has an important role in genetic counseling and for planning individualized treatment for sickle cell anemia.