Sirolimus has anti-carcinogenic properties and can be included in maintenance immunosuppressive therapy following kidney transplantation. We investigated sirolimus effects on cancer incidence among kidney recipients. The US transplant registry was linked with 15 population-based cancer registries and national pharmacy claims. Recipients contributed sirolimus-exposed time when sirolimus claims were filled, and unexposed time when other immunosuppressant claims were filled without sirolimus. Cox regression was used to estimate associations with overall and specific cancer incidence, excluding nonmelanoma skin cancers (not captured in cancer registries). We included 32604 kidney transplants (5687 sirolimus-exposed). Overall, cancer incidence was suggestively lower during sirolimus use (hazard ratio [HR]=0.88, 95% confidence interval [CI]=0.70-1.11). Prostate cancer incidence was higher during sirolimus use (HR=1.86, 95% CI=1.15-3.02). Incidence of other cancers was similar or lower with sirolimus use, with a 26% decrease overall (HR=0.74, 95% CI=0.57-0.96, excluding prostate cancer). Results were similar after adjustment for demographic and clinical characteristics. This modest association does not provide strong evidence that sirolimus prevents posttransplant cancer, but it may be advantageous among kidney recipients with high cancer risk. Increased prostate cancer diagnoses may result from sirolimus effects on screen detection. Using a linkage of the US transplant registry with cancer registries and national pharmacy claims, this study finds that sirolimus use after kidney transplantation was associated with a modest decrease in non-prostate cancer incidence.