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The relative efficacy of anti-IL-2 receptor antibodies (IL2R Abs) and antilymphocyte antibodies in preventing acute rejection and improving graft survival after renal transplantation is poorly defined. In particular, the benefits of these agents in specific subgroups, such as recipients with different degrees of HLA mismatch, are unknown. Using the SRTR database, we compared IL2R Abs to no induction and to antilymphocyte antibody induction in 48 948 first renal transplant recipients in the United States between 1998 and 2003 with respect to acute rejection and graft failure. IL2R Abs decreased acute rejection at 6 months (OR: 0.81(0.75–0.87)), and reduced graft failure (HR: 0.90(0.84–0.95)), compared to no induction over a follow-up of 1059 days. Compared to IL2R Abs, antilymphocyte Abs were associated with decreased acute rejection (OR: 0.90(0.83–0.99)) at 1 year, but were not associated with improved graft survival (OR: 1.08(1.00–1.18)) over a follow-up of 732 days. The benefit of IL2R Abs in reducing acute rejection increased significantly with greater HLA mismatch (p = 0.007). IL2R Abs remain an important option in the management of renal transplant patients, and may be particularly useful in specific patient subsets.