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Cancer continues to be an important cause of morbidity and mortality after renal transplantation. Unfortunately, risk factors for cancer have not been well defined.We examined risk factors for invasive, life-threatening malignancies among 1500 renal transplant recipients. Both univariate and multivariate Cox proportional hazards analyses were used.There were 87 tumors in 88 patients. Actuarial survival free of cancer was 95.9% at 5 years, 92.3% at 10 years, 86.6% at 15 years, and 82.6% at 20 years. Among multiple possible risk factors, the adjusted, relative risk attributable to age at transplantation (compared to age <45 years) was 2.00 (95% confidence interval: 1.21-3.30, P=0.007) for age ≥45 and <60 years (29.1% of total were in this age range), and 3.81 (95% confidence interval: 2.05-7.06, P<0.001) for age ≥60 years (11.6%). The relative risk attributable to pretransplant splenectomy (47.8%, now large abandoned) was 1.87 (95% confidence interval: 1.12-3.12, P=0.016). Patients with renal disease from type 1 diabetes had a lower risk of cancer, 0.19 (95% confidence interval: 0.05-0.08, P=0.015). A history of invasive cancer pretransplant (2.5%) increased the risk of posttransplant cancer to 2.38 (95% confidence interval: 1.18-4.83, P=0.015). Cigarette smoking was also associated with an increased risk, with each 10 pack-years smoked at transplant increasing the risk of cancer by 1.12 (1.02-1.21, P=0.016). The era when transplantation occurred, the type of prophylactic immunosuppression used, the occurrence of acute rejection, or its treatment did not alter the risk of cancer.The risk of cancer continues to increase 15-20 years after transplantation. The identification of splenectomy as a new risk factor, even several years after this immunosuppression strategy has been abandoned, demonstrates that the risk of immunosuppression may take years to become manifest. Efforts to reduce immunosuppression, particularly for patients ≥45 years of age at transplant, along with a greater effort to discourage cigarette smoking, may help reduce the risk of cancer after renal transplantation.