The clinical and hematologic features of sickle cell disease in two groups of patients of different ancestral origin, but living in the Eastern Province of Saudi Arabia, are presented. Twenty-eight patients of southwestern origin were matched for gender, age, and diagnosis with an equal number of patients of eastern origin. The disease was diagnosed in all patients at birth, and follow-up study was done on a regular basis. Despite being born and living in the same environment (Eastern Province), patients of southwestern origin had more severe clinical features, consistently lower hemoglobin levels, and higher reticulocyte counts, suggesting more severe hemolysis. We conclude that there are at least two distinct forms of sickle cell disease in the Eastern Province of Saudi Arabia and that the variability of the disease in early childhood is more likely related to genetic than to environmental factors.