BACKGROUND: Plasma carboxypeptidase B2 (CPB2) is an enzyme that regulates protein activities by cleaving C-terminal amino acids. With its anti-inflammatory and antifibrinolytic properties, CPB2 can have protective or harmful effects on disease. We investigated the impact of CPB2 on long-term outcomes after kidney transplantation. METHODS: This observational cohort study involved 1271 renal transplant pairs from the University Medical Center Groningen in The Netherlands and analyzed 4 CPB2 gene (CPB2) polymorphisms (rs2146881, rs3742264, rs1926447, and rs3818477) and 2 complement polymorphisms (rs2230199 and rs17611) in both donors and recipients, in relation to 15-y allograft survival. RESULTS: The CPB2 rs3742264 polymorphism in the donor was associated with a reduced risk of graft loss after kidney transplantation (hazard ratio: 0.71 for the CPB2 147T variant; 95% confidence interval, 0.55-0.93; P = 0.014). This association remained significant after comprehensive adjustments. However, the protective effect of the CPB2 147T variant in the donor could be mitigated by the hazardous effect of gain-of-function complement polymorphisms. Additionally, we compiled a genetic risk score based on the 4 CPB2 variants in the recipients and donors. This genetic risk score was independently associated with long-term allograft survival and substantially improved risk prediction for graft loss beyond currently used clinical predictors. CONCLUSIONS: Kidney allografts possessing the CPB2 147T variant have a lower risk of graft loss following kidney transplantation. Moreover, our findings suggest that CPB2 might protect against graft loss by inactivating complement anaphylatoxins.