Therapy related secondary malignancies after NHL are well characterized in the HIV negative population. The increased risk of secondary leukemia is most commonly associated with alkylating agents, topoisomerase II inhibitors and radiation therapy. We describe 2 patients with HIV-associated Burkitt's lymphoma who subsequently developed acute leukemia.Case Report 1: An HIV positive 60 yr old male was diagnosed with Burkitt's lymphoma five years after beginning antiretroviral therapy. Lymph node flow cytometry demonstrated: CD10+, CD19+, CD20+, KAPPA+. He achieved a complete remission after completing the Vanderbilt regimen (cyclophosphamide, methotrexate, bleomycin, vincristine, and doxorubicin) (McMaster M, et al. J Clin Oncol . 1991: 9:941–946). Eight years later, he presented with acute myelomonocytic leukemia (M4) after a myelodysplastic prodrome. Flow cytometry demonstrated CD11c+, CD13+, CD33+, CD34+, CD 64+ and cytogenetics showed 5q(−) and 20q(−). He received induction chemotherapy with arsenic trioxide and low dose cytarabine. He did not achieve a remission, and died 2 months later.Case Report 2: A 45 yr old male presented with severe abdominal pain, and fever. During laparotomy, he was found to have a cecal mass consistent with Burkitt's lymphoma. A bone marrow biopsy also showed Burkitt's lymphoma: CD10+, CD19+, CD20+, CD22+, CD 38+, CD45+, CD71+. He was subsequently diagnosed with HIV with a CD4 count of 60/uL. He was treated with CODOX-M (cyclophosphamide, doxorubicin, vincristine, methotrexate, IT cytarabine, IT methotrexate) and IVAC (Ifosfamide, etoposide, cytarabine, IT methotrexate) (Magrath I, et al. J Clin Oncol 1996; 14:925–934) achieving a CR. He remained on antiretroviral therapy throughout his course. Two years later, he presented with thrombocytopenia. A bone marrow aspirate was consistent with precursor B-cell ALL CD19+, CD34+, CD79a+ and TdT+ distinct from the previous Burkitt's lymphoma. He was treated with the L20 (Clarkson B, et al. Haematol Blood Transfus 1990; 33:397–408) protocol achieving a durable CR. He continued his retroviral therapy during his treatment.Conclusions: HIV positive patients have an increased propensity to develop malignancy independent of prior chemotherapy or radiotherapy exposure. In the era of HAART, the survival of HIV positive patients has markedly improved. Although the role of chemotherapy and radiation therapy are well documented as causative agents of neoplasia, the risk of HAART therapy with toxicity of nuclear, cytoplasmic and cell membrane effects potentially inducing malignancies is less well defined. Many of these agents are considered oncogenic in animal models but have not been proven to cause tumors in humans. However, it is conceivable, given the cellular toxicities of antineoplastic and antiretroviral therapy, that in combination they could cause myelodysplasia or further lymphodysplasia. It is too early to know if HIV patients are at a greater risk for development of secondary malignancies as a long-term complication of chemotherapy. However, because recent studies have demonstrated that HIV+ patients on highly active antiretroviral therapy (HAART) have comparable responses to chemotherapy compared to HIV negative patients, we recommend that patients continue HAART while receiving treatment for malignancy. Close surveillance for the appearance of secondary leukemias is warranted.