IGF-binding protein-2 (IGFBP-2) is a 36-kDa protein that binds to the IGFs with high affinity. To determine its role in bone turnover, we compared Igfbp2^−/− mice with Igfbp2^+/+ colony controls. Igfbp2^−/− males had shorter femurs and were heavier than controls but were not insulin resistant. Serum IGF-I levels in Igfbp2^−/− mice were 10% higher than Igfbp2^+/+ controls at 8 wk of age; in males, this was accompanied by a 3-fold increase in hepatic Igfbp3 and Igfbp5 mRNA transcripts compared with Igfbp2^+/+ controls. The skeletal phenotype of the Igfbp2^−/− mice was gender and compartment specific; Igfbp2^−/− females had increased cortical thickness with a greater periosteal circumference compared with controls, whereas male Igfbp2^−/− males had reduced cortical bone area and a 20% reduction in the trabecular bone volume fraction due to thinner trabeculae than Igfbp2^+/+ controls. Serum osteocalcin levels were reduced by nearly 40% in Igfbp2^−/− males, and in vitro, both CFU-ALP⁺ preosteoblasts, and tartrate-resistant acid phosphatase-positive osteoclasts were significantly less abundant than in Igfbp2^+/+ male mice. Histomorphometry confirmed fewer osteoblasts and osteoclasts per bone perimeter and reduced bone formation in the Igfbp2^−/− males. Lysates from both osteoblasts and osteoclasts in the Igfbp2^−/− males had phosphatase and tensin homolog (PTEN) levels that were significantly higher than Igfbp2^+/+ controls and were suppressed by addition of exogenous IGFBP-2. In summary, there are gender- and compartment-specific changes in Igfbp2^−/− mice. IGFBP-2 may regulate bone turnover in both an IGF-I-dependent and -independent manner.