We have analyzed the incidence and risk factors of developing a secondary malignancy after total body irradiation (TBI) and hematopoietic stem cell transplantation (HSCT). From March 1986 to December 2002, 205 patients received TBI as a part of the HSCT conditioning regimen. TBI was administered in 6 fractions, twice a day, up to a total dose of 12 Gy, with a median dose rate of 11.44 cGy/min. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 119 patients and the other 86 patients received an autologous hematopoietic stem cell transplantation (AHSCT). Median age was 30 years (5–63). We have calculated the cumulative incidence of solid tumors and secondary hematologic malignancies among these patients. Death due to noncancerous causes and patients lost to follow-up were entered as a competitive risk. With a median follow-up of 32 months (0.2–229)- including patients deceased in the first three months- 13 (6.3%) developed a secondary malignancy, 7 of them (3.4%) developed a solid tumor and 6 (2.9%) developed a secondary hematologic malignancy. The 7 patients who developed a solid tumor-1 glioblastoma, 2 head and neck carcinoma, 2 basocelular carcinoma, 1 osteosarcoma and 1 cervical intraepithelial neoplasia- had received an allo-HSCT. The 6 patients that developed a secondary hematologic malignancy- 5 therapy-related leukemia/myelodisplasia (t-AML/MDS) and 1 B cell non Hodgkin’s lymphoma- had received an AHSCT. The overall probability of developing a secondary malignancy after HSCT is 2.5% at 3 years (95% confidence interval (CI) 1.1– 6); 5% at 10 years (95% CI 2.6–9.3), and 9% at 15 years (95% CI 5–16.5). The probability of developing a solid tumor after HSCT is 0.5% at 3 years (95% CI 0.1–3.6), 1.8 % at 10 years (95% CI 0.6–5.5), and 6 % at 15 years (95% CI 2.6–13.7) and the probability of developing a secondary hematologic malignancy is 2 % at 3 years (95% CI 0.8–5.3), and 3,1 % at 10 and 15 years (95% CI 1.4–6.9). Median time to develop a solid tumor was 134 months (29–229). Median time to develop a secondary hematologic malignancy was 31 (3–60) months. Multivariate analysis proved that allo-HSCT was the only risk factor of developing a solid tumor, and that AHSCT and advanced age were risk factors of developing secondary hematologic malignancy (mean age 30 vs. 50 years ). To conclude, the probability of developing a solid tumor after HSCT is higher if an allo-HSCT has been performed and increases with time. AHSCT and advanced age are risk factors for the development of a secondary hematologic malignancy, a risk that decreases 5 years after AHSCT.