We report the smallest infant (7.5 kg) to receive intensive plasma exchange (52 PEs) therapy as treatment of autoimmune hemolytic anemia (AIHA). PE temporarily reduces circulating autoantibody levels and can be an effective adjunctive therapy with corticosteroids and cytotoxic drugs or other immuno-suppressants. Although his clinical course was prolonged and complicated by cytomegalovirus infection with spontaneous perforation of his colon, his recovery was complete. He has remained healthy for more than 2 years. Because of his small size, calcium gluconate was added to replacement fluids and calcium levels closely monitored. The apheresis machine and tubing were routinely primed with red blood cells and FFP substituted for 5% human albumin during the second half of all procedures to maintain adequate levels of procoagulant. Our experience suggests that intensive PE is helpful in controlling severe AIHA and should be considered even for very small patients.