Complement factor C5a has two known receptors, C5aR mediating pro-inflammatory effects and C5L2, a potential C5a scavenger. We previously identified C5a/C5aR signaling as a potent profibrotic pathway in the kidney. Here we tested for the first time the role of C5L2 in renal fibrosis. In unilateral ureteral obstruction (UUO)-induced kidney fibrosis, the expression of C5aR and C5L2 increased similarly and gradually as fibrosis progressed and was particularly prominent in injured dilated tubules. Genetic deficiency of either C5aR or C5L2 significantly reduced UUO-induced tubular injury. Expression of key pro-inflammatory mediators, however, significantly increased in C5L2- compared to C5aR-deficient mice, but this had no effect on the number of renal infiltrating macrophages or T-cells. Moreover, in C5L2-/--mice the cytokine and MMP-inhibitor TIMP-1 was specifically enhanced. Consequently, in C5L2-/--mice the degree of renal fibrosis was similar to WT, albeit with reduced mRNA expression of some fibrosis-related genes. In contrast, C5aR-/--mice had significantly reduced renal fibrosis compared to WT- and C5L2-/--mice in UUO. In vitro experiments with primary tubular cells demonstrated, that deficiency for either C5aR or C5L2 led to a significantly reduced expression of tubular injury- and fibrosis-markers. Vice versa, stimulation of WT tubular cells with C5a significantly induced the expression of these markers, whereas absence of either receptor abolished this induction. In conclusion, in experimental renal fibrosis C5L2 and C5aR both contribute to tubular injury, and, while C5aR acts profibrotic, C5L2 does not play a role in extracellular matrix accumulation, arguing against C5L2 functioning simply as a decoy receptor.