Immunosuppressive drug therapy has been identified as one etiological factor in the increased incidence of and deaths from malignancies in renal transplant recipients. In animal models, calcineurin inhibitors have a positive growth effect, whereas target-of-rapamycin (TOR) inhibitors have a negative growth effect on malignant cells. A multivariate analysis of posttransplant malignancies in 33,249 deceased donor primary solitary renal recipients reported by 264 kidney transplant programs to the Organ Procurement and Transplantation Network database from July 1, 1996 to December 31, 2001 was performed. Data were censored at 963 days to allow comparable follow-up time among drug treatment groups. The incidence and relative risks of any de novo malignancy (skin and solid) and for non-skin solid malignancies in patients receiving TOR inhibitors compared to patients receiving calcineurin inhibitors were the primary endpoints. The incidence rates of patients with any de novo posttransplant malignancy were 0.60% with sirolimus/everolimus alone, 0.60% with sirolimus/everolimus + cyclosporine/tacrolimus, and 1.81% with cyclosporine/tacrolimus (P<0.0001); the rates with a de novo solid tumor were 0%, 0.47%, and 1.00%, respectively. In the Cox regression model the relative risk associated with sirolimus/everolimus immunosuppression for any de novo cancer was 0.39 (95% CI: 0.24-0.64; P=0.0002) and for de novo solid cancer was 0.44 (0.24-0.82; P=0.0092). Other significant risk factors were male sex, adult age group, white race, and history of a malignancy. Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and non-skin solid malignancy.