Anin vitroco‐culture system composed of bone marrow‐derived mononuclear phagocytes (obtained from endotoxin‐responsive mice) and45Ca‐labeled calvaria (obtained from endotoxin‐hyporesponsive mice) was established in order to examine the direct effect of bacterial endotoxin on bone resorption mediated by mononuclear phagocytes. Co‐cultures treated with endotoxin exhibited a significant increase in bone resorption assessed in terms of the %45Ca released. This increase was observed in the absence of direct contact between the mononuclear phagocyte population and bone, indicating that enhanced resorption occurred as a function of soluble factors secreted by mononuclear phagocytes in response to endotoxin. Co‐cultures which contained devitalized45Ca‐calvaria failed to exhibit an increase in the %45Ca released following endotoxin treatment. Consequently, the soluble factors secreted by endotoxin‐stimulated mononuclear phagocytes appeared to modulate the activity of endogenous bone‐resorbing cells. Two soluble factors with bone‐resorbing activity were distinguished upon subsequent analysis. These results suggest that the interaction between plaque‐associated bacterial endotoxin and mononuclear phagocytes may have important consequences relevant to the resorption of alveolar bone characteristic of chro