Sickle cell trait revisited. Variability in the clinical severity of sickle cell diseases is often genetically determined. Coexistent alpha-thalassemia decreases some, but not all, associated morbid complications. Polymorphisms within the beta-globin-like gene cluster influence disease severity by varying gamma-gene expression and the amount of Hb F within the cells. Few persons with the sickle cell trait experience adverse consequences attributable to the beta s gene. Is this also due to genetic factors? A literature search failed to answer this question. It is intriguing, however, that reported associations of sickle cell trait and splenic infarction have occurred exclusively in males and mostly in whites. Plausible but scanty data suggest that splenic infarction, hematuria, and reduced renal concentrating ability may be associated with higher amounts of Hb S. Therefore, alpha-thalassemia may be protective. No evidence was found that the amount of Hb S influenced the incidence of sudden death after exertion or that increased amounts of Hb F accounted for protection against any complications. More detailed reporting of biochemical and genetic evaluations of persons with sickle cell trait who experience related clinical events may lead to a better understanding of risks in subpopulations of persons carrying a single beta s gene. 