C5a is a potent proinflammatory agonist that mediates renal ischemia reperfusion (IR) injury, but the potential for modulating chronic post-ischemic fibrosis and use of therapeutic antagonist are undefined. Here we determine whether C5a receptor 1 (C5aR1) signaling is essential to the development of post-ischemic fibrosis and if it is a valid target for therapeutic blockade with soluble receptor antagonist. C5aR1 is required for the development of renal tubulointerstitial fibrosis in a murine model of renal ischemia/reperfusion injury. Deficiency of C5aR1 protected mice from the development of the fibrosis. This protection was associated with attenuated deposition of extracellular matrix components (fibronectin, collagen I), reduced cellular infiltrates (CD45, F4/80), and gene expression of proinflammatory and profibrogenic mediators in the kidney. In an in vitro model of hypoxia/reoxygenation, C5a stimulation caused renal fibroblast proliferation and activation, and upregulated gene expression of interleukin-1α (IL-1α), IL-6 and transforming growth factor-α (TGF-α) in renal tubular epithelial cells and monocytes/macrophages. Administration of a C5aR1 antagonist (PMX53) significantly reduced renal injury and tubulointerstitial fibrosis. Thus, our results demonstrate a pathogenic role for C5aR1 in the progression of tubulointerstitial fibrosis following renal IR injury and support that C5aR1-mediated local inflammatory responses to hypoxic renal injury contribute to tubulointerstitial fibrosis through several cellular pathways, namely, promoting tubule injury, interstitial fibroblast proliferation and epithelial-to-mesenchymal transition of renal tubular epithelial cells. Our results also suggest the C5a-C5aR1 interaction is a therapeutic target for chronic post-ischemic fibrosis.