One of the most serious complications of successful treatments for Hodgkin's disease is an increased incidence of acute nonlymphocytic leukemia (ANLL) and other malignancies. A retrospective analysis carried out on 1032 consecutive patients with Hodgkin's disease admitted to our Institute between 1965 and 1978 and treated with radiotherapy (RT) or chemotherapy or both modalities revealed that within 10 yr from initial therapy. ANLL was documented in 3% of patients, and over a comparable period of time 7.9% of patients developed other malignancies. ANLL was observed only in patients treated with chemotherapeutic regimens containing alkylating agents and/or procarbazine either alone (2.3%) or associated with RT (4%). Other second tumors were documented in patients given RT with or without chemotherapy. No second malignancies were observed in patients given ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) with or without RT. The incidence of ANLL was higher in patients given chemotherapy as salvage treatment upon relapse following primary irradiation (6.1%) compared to patients initially treated with combined modality (1.5%). The difference, however, failed to reach statistical significance. Since our analysis supports the evidence of a major role played by alkylating agents, procarbazine, and RT in inducing second malignancies, regimens not containing there drugs or their administration through treatments of different intensity warrant careful consideration.