Details of the cellular and biochemical mechanisms involved in focal destruction of bone at sites of tumor osteolysis are unknown. It has been shown that tumors from sarcoma (2472) cell lines induce focal osteolysis in mice by stimulating formation and activation of osteoclasts. In this report, the influence of 2472 tumors on the skeletons of osteoclast‐deficient animals (op/op) was studied. After op/op femora had been inoculated with 2472 cells, tumors developed and focal osteolysis occurred. There were more osteoclasts per histologic section in sham‐injected femora (19 ± 5) than in tumor‐bearing femora (412 ± 129) (p < 0.05). The size of the osteoclasts also increased from 304 ± 81 μm2 in sham‐injected limbs to 407 ± 62 μm2 in tumor‐bearing limbs (p < 0.001). Conditioned media from 2472 op/op tumor explants contained macrophage colony‐stimulating factor. A deficiency of osteoclasts in op/op mice is the result of the absence of this factor; therefore, these data introduce the possibility that macrophage colony‐stimulating factor derived from 2472 tumor may be responsible for directing osteoclast‐mediated osteolysis at sites of the tumor.