Risk of malignancy with long-term immunosuppression in renal transplant recipients. Improvements in immunosuppressive regimens have significantly enhanced patient and graft survival in renal transplant recipients. However, susceptibility to neoplastic disorders is increased as a consequence of prolonged immunosuppression. Available data pertaining to cancer risks in renal transplant recipients have been inconsistent, and much of it is derived from international studies, which may not be truly representative of the United States population. We studied a total of 1979 transplants performed in 1739 patients from a single center in the United States with a mean follow-up of 6.1 years, and a total of 9852 person-years' follow-up. The mean age at the time of diagnosis of cancer was 50 years, and the mean interval between transplant and diagnosis of cancer was 95 months. Older patients receiving a transplant had a significantly higher risk for developing cancer as opposed to younger patients (RR 6.2 for >60 years compared with <40 years). When compared with the general population using data from the Surveillance, Epidemiology and End Results (SEER) registry, the overall risk for nonskin malignancies was modestly increased in our transplant recipients, with a standardized incidence ratio (SIR) of 1.4 (P = 0.01). When stratified by age groups, younger age at transplant (<40 years) had the highest SIR, at 2.3 (P < 0.001). Similarly, duration post-transplant >10 years had an SIR of 2.4 (P < 0.001). We believe that this study is representative of the United States' renal transplant population, and highlights the need for reduced immunosuppression in the long-term and increased vigilance for cancers in younger patients receiving renal transplantation.