Macrophage colony-stimulating factor (M-CSF) is a hematopoietic growth factor that plays a critical role in early osteoclastogenesis. To characterize the skeletal effects of M-CSF, we administered soluble M-CSF to mice. It was hypothesized that M-CSF would stimulate bone formation through coupled activity of osteoclasts and osteoblasts. Twenty-four male C57BL/6 J mice (n = 12/group, aged 7 weeks) received subcutaneous injections of human M-CSF [5 mg/(kg day)] or inert vehicle (VEH) for 21 days. M-CSF increased serum bone turnover markers (+57% TRAP-5b and +44% osteocalcin). Microcomputed tomography revealed an anabolic effect on tibial trabecular bone, with higher bone volume fraction (+35%), connectivity density (+79%), and number (+18%), as well as lower trabecular separation (-18%). M-CSF had no significant effect on cortical bone mineral content, geometry, or strength. There was no change in quantitative histomorphometry parameters of femoral cortical bone. These results reveal the complex, site-specific effects of M-CSF. In particular, we have demonstrated an anabolic effect of M-CSF on trabecular bone achieved through coupled activation of osteoblasts. However, in contrast to previous studies, M-CSF was found to have no effect on cortical bone. M-CSF was demonstrated to significantly influence both bone modeling and remodeling in relatively young animals.