Soluble molecules including complement components have been shown to facilitate the clearance of dying cells by phagocytes, a process that is important in preventing tissue damage and autoimmunity. However, the extent to which complement is involved in this process and the relative contribution of each of the complement activation pathways is not fully understood. We examined the role of complement in the recognition/uptake of apoptotic thymocytes by murine bone marrow-derived macrophages (BMDM) in vitro using sera from gene-targeted mice. We found this process to be IgM- and complement-dependent, especially when the apoptotic cell-to-BMDM ratio was low, and the level of C3 deposition on apoptotic cells correlated closely with their uptake. The addition of C1q rectified the phagocytic defect seen in the presence of C1q-deficient serum in vitro but had no effect on the phagocytic defect observed with serum deficient in both IgM antibodies and C1q. Similarly, complement activation by IgM antibodies was essential for in vivo C3 deposition on apoptotic cells and their uptake by peritoneal macrophages. Hence, the efficient uptake of dying cells by BMDM requires IgM antibodies and complement.