We examined integrated national transplant registry, pharmacy fill, and medical claims data for Medicare‐insured kidney transplant recipients in 2000–2011 (n = 45 164) from the United States Renal Data System to assess the efficacy and safety endpoints associated with seven early (first 90 days) immunosuppression (ISx) regimens. Risks of clinical complications over 3 years according to IS regimens were assessed with multivariate regression analysis, including the adjustment for covariates and propensity for receipt of a nonreference ISx regimen. Compared with the reference ISx (thymoglobulin induction with tacrolimus, mycophenolate, and prednisone maintenance), sirolimus‐based ISx was associated with significantly higher three‐year risks of pneumonia (adjusted hazard ratio, aHR 1.45; P < 0.0001), sepsis (aHR 1.40; P < 0.0001), diabetes (aHR 1.21; P < 0.0001), acute rejection (AR; adjusted odds ratio, aOR 1.33; P < 0.0001), graft failure (aHR 1.78; P < 0.0001), and patient death (aHR 1.40; P < 0.0001), but reduced skin cancer risk (aHR 0.71; P < 0.001). Cyclosporine‐based IS was associated with increased risks of pneumonia (aHR 1.17; P < 0.001), sepsis (aHR 1.16; P < 0.001), AR (aOR 1.43; P < 0.001), and graft failure (aHR 1.39; P < 0.001), but less diabetes (aHR 0.83; P < 0.001). Steroid‐free ISx was associated with the reduced risk of pneumonia (aHR 0.89; P = 0.002), sepsis (aHR 0.80; P < 0.001), and diabetes (aHR 0.77; P < 0.001), but higher graft failure (aHR 1.35; P < 0.001). Impacts of ISx over time warrant further study to better guide ISx tailoring to balance the efficacy and morbidity.