This large prospectively conducted observational cohort study examined the risk of lymphoma and other malignancies with mycophenolate mofetil (MMF) in de novo renal transplant recipients. A total of 6751 patients receiving MMF, and an equal number of matched controls receiving non-MMF-based immunosuppression, were identified from two large registries (Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) and Collaborative Transplant Study (CTS)) and followed for 3 years. The primary endpoint was development of lymphoma. Secondary endpoints included development of any malignancy. There was no evidence of any increased risk of developing lymphoma or malignancy with MMF. The risk of developing lymphoma with MMF compared with the non-MMF cohort was not higher in either the CTS registry (relative risk (95% confidence interval); 0.4 (0.17–0.94)) or the OPTN/UNOS registry (1.04 (0.61–1.78)). In the MMF group, there was a trend toward a lower risk of malignancy in both registries (OPTN/UNOS 0.86 (0.69–1.07); CTS 0.79 (0.61–1.02)) and a significant increase in time to malignancy in the CTS dataset (p < 0.026). This study has demonstrated that MMF is not associated with an increased risk of lymphoma or other malignancies post-renal transplant, and may even be associated with a lower risk in some populations.