Second primary cancers are a serious late occurrence for patients surviving Hodgkin's disease (HD). In addition to previously described risk factors such as age, gender, clinical stage, and treatment modalities, splenectomy was found to correlate with an increase in risk for secondary acute leukemia. We assumed that splenic irradiation inducing functional hyposplenia and splenectomy could have similar consequences on second cancer risk. We studied a series of 892 continuously disease-free HD adult patients treated at a single institution between 1960 and 1984. The risk of second cancer was analyzed (1) relative to the general population and (2) between risk subgroups using the Cox proportional hazards model. Fifty-six patients developed a second cancer (8 acute leukemias, 3 myelodysplastic syndromes, 8 non-Hodgkin's lymphomas, and 37 solid tumors; basal cell and in situ cervix carcinomas were excluded). The 15-year cumulative incidence rate (with 95% confidence limits) was 13.2% (9.3% to 17.2%). Relative to the general population incidence data, the risk of second cancer was multiplied by 4.68 (3.51 to 6.12; P < .001); it was multiplied by 2.80 (1.63 to 4.48; P < .001) in patients whose spleen was not treated and multiplied by 6.87 (4.81 to 9.51; P < .001) in splenectomized patients or patients whose spleen was irradiated. Multivariate regression analysis that controlled for confounding variables (age, gender, clinical stage, extent of radiation therapy, and chemotherapy regimen) showed that, in addition to age above 40 years (relative risk [RR] = 3.72; P < .001), combination of MOPP chemotherapy and regional irradiation (RR = 4.99; P = .015) and combination of MOPP chemotherapy and extended irradiation (RR = 10.86; P < .001), splenic irradiation (RR = 3.67; P = .003), and splenectomy (RR = 2.54; P = .018) also significantly correlated with an increased risk. The results of this hospital-based registry study strongly suggest that splenic irradiation and splenectomy might increase the risk for treatment-related second cancer. These findings, if confirmed, have to be considered in future HD treatment policies.