Some of the constant characteristics of Mendelian autosomal dominant diseases are non-penetrance and variable expressivity. However, sickle cell anaemia (SSA) is probably unique among the autosomal recessive diseases in the variable expressivity of its natural history. It therefore seems likely that other factors extraneous to the sickle gene locus may play a part in full phenotypic expression of SSA. To find out the possible role of red cell antigens in the variable expressivity of SSA, ABO and Rhesus antigens have been determined in 200 electrophoreücally confirmed Hb SS patients and 250 sex- and age-matched Hb AA controls; the Hb SS group was subsequently divided into ‘mild’ and ‘severe’ sicklers and the results analysed. There were no statistically significant differences in the ABO and Rhesus blood group antigen distributions between the sicklers and Hb AA controls. There were also no correlations between the severity of the Hb SS disease and either the ABO or Rhesus group distributions. We conclude from these studies that ABO or Rhesus blood group antigens do not have significant moderating effect on the natural history of SSA.