BACKGROUND Immunosuppression plays an essential role to overcome immune-related allograft rejection, but it also causes some nephrotoxicity. This study aimed to investigate how the immunosuppressant combinations affect graft outcomes in kidney transplant recipients. METHODS A nationwide population-based cohort study using the Taiwan National Health Insurance Database was conducted. A total of 3,441 kidney transplant recipients who underwent kidney transplantation during the targeted period were included. The effects on graft outcomes contributed by conventional immunosuppressants, including corticosteroid, calcineurin inhibitors, antimetabolite purine antagonists, and mammalian target of rapamycin inhibitors, were compared. RESULTS A total of 423 graft failures developed after the index date. Therapy regimens incorporated with purine antagonists had a comparable reduction of graft failure among four main drug groups regardless of whether they were given as monotherapy or in combination (adjusted hazard ratio: 0.52, 95% confidence interval: 0.42-0.63). Corticosteroid was found to have inferior effects among four groups (adjusted hazard ratio: 1.67, 95% confidence interval: 1.28-2.21). Furthermore, all 15 arrangements of mutually exclusive treatment combinations were analyzed by referencing with corticosteroid monotherapy. As referenced with steroid-based treatment, regimens incorporated with purine antagonists all have superior advantage on graft survival regardless of whether given in monotherapy (65% of graft failure reduced), dual therapy (48%-67% reduced), or quadruple therapy (43% reduced). In all triple therapies, only corticosteroid combined with calcineurin inhibitor and purine antagonist demonstrated superior protection on graft survival (52% of graft failure reduced). CONCLUSIONS The results may recommend several superior regimens for contributing to graft survival, and for supporting a steroid-minimizing strategy in immunosuppression maintenance.