The survival of patients with Hodgkin's disease has dramatically improved over the past 30 years because of advances in treatment. However, concern for the risk of long-term complications has resulted in a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. One major consequence of successful treatment of Hodgkin's disease is the development of second malignant neoplasms. We sought to determine the factors most important for development of second tumors in pathologically staged and treated Hodgkin's disease patients followed for long intervals to provide background information for future clinical trials and guidelines for routine patient follow-up. Between April 1969 and December 1988, 794 patients with laparotomy staged (PS) IA-IIIB Hodgkin's disease were treated with radiation therapy (RT) alone or combined radiation therapy and chemotherapy (CT). There were 8,500 person-years of follow-up (average of 10.7 person-years per patient). Age and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed to expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. Seventy-two patients have developed a second malignant neoplasm. Eight patients developed acute leukemia, 10 had non-Hodgkin's lymphoma (NHL), and 53 patients developed solid tumors at a median time of 5 years, 7.25 years, and 12.2 years, respectively, after Hodgkin's disease. One patient developed multiple myeloma 16.5 years after Hodgkin7s disease. The relative risk (RR) of developing a second malignancy was 5.6. The absolute excess risk per 10,000 person-years (AR) of developing a second malignancy was 69.6 (7.0% excess risk per person per decade of follow-up). The highest RR occurred for the development of leukemia (RR = 66.2), however because of the low expected risk, the AR was only 9.3. The RR of solid tumors after Hodgkin's disease was lower (4.7); however, the AR was greater (49) than for acute leukemia. Among the solid tumors, breast, gastrointestinal, lung, and soft tissue cancers had the highest absolute excess risks. The risk for developing breast cancer after Hodgkin's disease was greatest in women who were under the age of 25 at treatment. The most significant risk factor for the development of both leukemia and solid tumors was the combined use of radiation therapy and chemotherapy. The RR following RT alone was 4.1 (AR = 51.1); for RT + CT (initially or at relapse) the RR was 9.75 (P < 0.05, nonoverlapping confidence limits, AR = 123.9). Survival following development of a second malignancy was poor in patients with leukemia, gastrointestinal tumors, lung cancer, and sarcoma. Survival from other malignancies including NHL and breast cancer was more encouraging. Second malignant neoplasms are a major cause of late morbidity and mortality following treatment for Hodgkin's disease. The most significant risk factor for the development of second tumors is the extent of treatment for Hodgkin's disease. Recommendations are presented for both prevention and early detection of these tumors.