Nephrotoxicity is a common complication of cisplatin chemotherapy that limits its clinical use; however, the mechanisms underlying cisplatin-mediated nephrotoxicity are not fully understood. In this study, we aimed to investigate the role of anaphylatoxin C5a in the pathogenesis of cisplatin's nephrotoxicity. Our data show that cisplatin-induced renal injury is significantly reduced in C5- or C5aR-deficient mice. C5 or C5a pretreatment restores the sensitivity to cisplatin-induced nephrotoxicity in C5-deficient mice. Administration of cisplatin in wild-type mice triggers the increased renal expression of multiple cytokines and caspases. Such induction is diminished in C5-deficient mice, which is restored by pretreatment with C5 or C5a proteins. Interestingly, cisplatin-induced renal injury is similar between wild-type and CD59 knock out mice. Cisplatin-induced formation of membrane attack complexes (MACs) in the kidney is diminished in C5-deficient mice, but not in C5aR-deficient mice. In conclusion, our findings suggest that C5a plays an important role in the pathogenesis of cisplatin's nephrotoxicity. C5a likely binds to C5aR, which leads to induction of proinflammatory cytokines and inflammation. The formation of MACs does not appear to contribute to the nephrotoxicity of cisplatin based on our study results.