Autologous hematopoietic stem cell transplantation (AHCT) for relapsed/refractory aggressive non-Hodgkin lymphoma (NHL) results in long-term disease-free survival in 40-50% of patients. The incidence of and risk factors for second cancer development in these patients have not been well studied. We analysed 372 patients with relapsed/refractory aggressive NHL who underwent AHCT from 1987 to 2006. Median age at AHCT was 50 years (range 19-70). Most patients (74%) received two chemotherapy regimens before transplant. High-dose chemotherapy consisted of etoposide and melphalan in 95% of patients and 16% received total body irradiation. Thirty-two patients (9%) developed a second cancer (19 hematologic, 13 solid tumors). The probability of second cancer at 3 and 10 years post-AHCT was 4.4% and 12.9%, respectively. When compared with the general population, the relative-risk of acute myeloid leukemia and new solid tumor was 13.2 (p < 0.0001) and 2.3 (p = 0.0013). Salvage therapy using mini-BEAM was significantly associated with second cancer development (p = 0.004). In conclusion, second cancers are a significant cause of late morbidity and mortality patients treated with AHCT with curative intent, and appear increased in patients exposed to mini-BEAM chemotherapy.