Cellular mechanisms of bone resorption associated with skeletal metastasis are poorly understood. Human tumour-associated macrophages (TAMs) isolated from primary lung carcinomas were incubated on bone slices where they formed resorption lacunae after 14 days co-culture with a mouse marrow-derived stromal cell line (ST2) with added 1 alpha, 25-dihydroxy Vitamin D3 and dexamethasone. These co-cultures were associated with the formation of increased numbers of tartrate resistant acid phosphatase positive mononuclear and multinucleated cells. Similar cocultures of ST2 cells with normal alveolar macrophages did not result in lacunar resorption. Both in the presence and absence of ST2 cells, TAMs and normal alveolar macrophages produced roughening of the bone surface with exposure of mineralised collagen fibres. TAMs are capable of both low-grade surface resorption and high-grade lacunar resorption of bone, and a specific interaction with stromal cells is necessary for the latter to occur. TAMs may thus directly contribute to the bone resorption associated with skeletal metastasis.