It has been suggested that acquired abnormalities of the red cell membrane due to various injuries [azidothymidine (AZT) therapy, immunoglobulin coating of red cells, differentiation abnormalities of erythroid precursors] contribute to the onset of anaemia in HIV-infected patients. In vitro proteolysis of erythrocyte membrane proteins is regarded as a molecular marker of membrane damage induced in vivo by different agents. We therefore investigated in vitro proteolysis of ghosts derived from red blood cells of 30 HIV-infected patients. Considered collectively, there was no significant increase in in vitro proteolysis in ghosts from anaemic HIV patients. However, a significantly higher degree of in vitro self-digestion of RBC membrane proteins was evident in HIV-infected patients with spleen enlargement, but not in splenomegalic patients suffering from liver cirrhosis. Neither AZT therapy nor the presence of a positive direct antiglobulin test seemed to be directly associated with increased in vitro protein breakdown. The results seem to suggest damage of the red cell membrane in HIV infection, induced by injuries on red cells during their prolonged retention inside an enlarged spleen, while it seems unlikely that AZT therapy or immunoglobulin coating of red cells play major roles in red cell damage.