OBJECTIVES: To determine if blocking C5aR could effectively protect mice from UPEC induced kidney infection. METHODS: A well-established mouse model of ascending UTI leading to kidney infection was employed. C5aR antagonist (C5aRa, W54011) (250mg/kg) was given before the induction of infection by i.p. injection. Kidney infection was assessed in C5aRa or control reagent treated mice at 6, 24, 72h after bladder inoculation of UPEC. Bacteria load in kidneys was analysed by the agar plate assay. Tissue damage was assessed by histopathology. Leukocytes infiltration was analysed by immunochemical staining, tissue MPO activity assay and flow cytometry. Renal synthesis of cytokines/chemokines was analysed by RT-PCR. RESULTS:  Compared to control reagent treated mice, C5aRa treated mice, either from B6 or BALB/c background, exhibited significantly lower rates of kidney infection (B6: 37.5% vs 100% [n=16], BALB/c: 26% vs 87% [n=15]), reduced kidney tissue damage and gene expression of KC, IL-6 and TNF-α in kidney tissues. The reduction of kidney infection and tissue damage resulting from C5aR blockade was more profound at 48h and 72h post infection. C5aR blockade led a small reduction of neutrophil infiltration at 6h, but had no apparent effect on late time point. CONCLUSIONS: C5aR blockade effectively protected mice from UPEC-induced kidney infection suggesting that C5aR signal is a critical pathogenic factor in UTIs, thus representing a promising target for treating or preventing human UTIs.