BACKGROUND: Although several studies had examined secondary malignancies in patients with specific primary tumor types, to the authors' knowledge there are very few data examining the long-term sequelae of pelvic radiation as a whole. The goal of the current study was to examine the risk of treatment-associated leukemia and multiple myeloma in patients treated with pelvic radiotherapy. METHODS: Patients with invasive tumors of the vulva, cervix, uterus, anus, and rectosigmoid treated from 1973 to 2005 and recorded in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Patients were stratified based on receipt of pelvic radiotherapy. The incidence of secondary leukemia (except chronic lymphocytic leukemia) and multiple myeloma were examined. Multivariate Cox proportional hazards models and Kaplan-Meier curves were constructed to examine the association between pelvic radiation and the development of subsequent hematologic malignancies. RESULTS: A total of 199,268 individuals, including 66,896 (34%) who received pelvic radiotherapy and 132,372 (66%) not treated with radiation, were identified. In a Cox proportional hazards model adjusting for other risk factors, post-treatment leukemia was increased by 72% (hazard ratio [HR], 1.72; 95% confidence interval [95% CI], 1.37-2.15) in the patients who received pelvic radiotherapy. The risk of secondary leukemia peaked at 5 to 10 years after primary treatment (HR, 1.85; 95% CI, 1.40-2.44) and remained elevated even 10 to 15 years after initial treatment (HR, 1.50; 95% CI, 1.03-2.18). There was no significant association between radiation and the development of multiple myeloma (HR, 1.08; 95% CI, 0.81-1.44). CONCLUSIONS: Pelvic radiation was associated with an increased risk of secondary leukemia but did not appear to increase the risk of multiple myeloma. Cancer 2010;116:2486-92.