Drug administration causes from 16 to 18 per cent of cases of acquired immune hemolytic anemia. The pathogenesis of erythrocyte sensitization by drug-related antibody with or without fixation of complement is variable, and there is a relationship between the responsible drug, the mechanism of red cell sensitization, clinical manifestations and laboratory methods of diagnosis. Drugs such as phenacetin and quinidine form a complex with the antidrug antibody, and the immune complex attaches to red cells usually fixing complement and causing acute intravascular hemolysis. Other drugs (e.g., penicillins), when given in large doses, coat normal red cells in vivo and in some patients a high titer IgG anti-drug antibody develops which reacts with the coated cells. Hemolytic anemia may develop with red cell destruction being primarily extravascular. Cephalosporins cause positive direct antiglobulin tests in a small percentage of patients either by the same mechanism as penicillins or by modification of the red cell membrane leading to nonimmunologic absorption of serum proteins. Hemolytic anemia has been reported only rarely. A few drugs (notably alpha methyldopa) cause the development of autoimmune hemolytic anemia. Knowledge of clinical manifestations and laboratory aids to diagnosis is necessary to distinguish immunohematologic abnormalities caused by drugs from other causes.