A 32-year-old male presented with fever, mental status changes, renal dysfunction, cytopenias and hemolysis. His platelet count was 14,000/microL, hemoglobin 5.7 g/dL and LDH 2,636 U/L. He was diagnosed with thrombotic thrombocytopenic purpura (TTP) and also found to be HIV positive on admission. TTP was confirmed by a low von Willebrand factor-cleaving protease level, the gold standard test for TTP, which was 10-15%. No protease-specific antibody was detected. Treatment of this patient consisted of 23 plasmapheresis procedures and trials of vincristine and dextran-70. Despite therapy, the patient remained anemic and thrombocytopenic, though his mental status and renal abnormalities improved. Highly active anti-retroviral therapy (HAART) consisting of efavirenz, 3TC, and d4T was started. Only after plasma exchanges were discontinued and HAART was instituted did the cytopenias resolve. He continued to improve following discharge, and platelet count was 206,000/microL and hemoglobin, 12.5 g/dL one month after the initiation of HAART.