Components of innate immunity have recently been implicated in the regulation of developmental processes. Most strikingly, complement factors appear to be involved in limb regeneration in certain urodele species. Prompted by these observations and anticipating a conserved role of complement in mammalian regeneration, we have now investigated the involvement of complement component C5 in liver regeneration, using a murine model of CCl(4)-induced liver toxicity and mice genetically deficient in C5. C5-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis after exposure to CCl(4.) In addition, these mice showed a marked delay in the re-entry of hepatocytes into the cell cycle (S phase) and diminished mitotic activity, as demonstrated, respectively, by the absence of 5-bromo-2'-deoxyuridine incorporation in hepatocytes, and the rare occurrence of mitoses in the liver parenchyma. Reconstitution of C5-deficient mice with murine C5 or C5a significantly restored hepatocyte regeneration after toxic injury. Furthermore, blockade of the C5a receptor (C5aR) abrogated the ability of hepatocytes to proliferate in response to liver injury, providing a mechanism by which C5 exerts its function, and establishing a critical role for C5aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis.