Severely injured patients frequently suffer compromised fracture healing because of systemic post-traumatic inflammation. An important trigger of the posttraumatic immune response is the complement anaphylatoxin C5a, which acts via two receptors, C5aR1 and C5aR2, expressed on immune and bone cells. The blockade of C5a-mediated inflammation during the early inflammatory phase was demonstrated to improve fracture healing after severe injury. However, the distinct roles of the two complement receptors C5aR1 and C5aR2 in bone has to date not been studied. Here, we investigated bone turnover and regeneration in mice lacking either C5aR1 or C5aR2 in a model of isolated fracture and after severe injury, combining the fracture with an additional thoracic trauma. Both C5aR1-/- and C5aR2-/- mice displayed an increased bone mass compared to wild-type controls due to reduced osteoclast formation and increased osteoblast numbers, respectively. Following fracture, the inflammatory response was differently affected in these strains: It was decreased in C5aR1-/- mice but enhanced in C5aR2-/- mice. Both strains exhibited impaired fracture healing, disturbed osteoclastogenesis and delayed cartilage-to-bone transformation. Thus, our data suggest that C5aR1 and C5aR2 differentially regulate the immune response after fracture and are required for effective cartilage-to-bone transformation in the fracture callus and for undisturbed bone healing.