Suppressor of cytokine signaling-2 (SOCS-2) is a member of the suppressor of cytokine signaling family, implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal transduction pathway. We have previously reported that SOCS-2-/- mice display an increased longitudinal skeletal growth associated with a deregulated GH/IGF-I signaling. The aim of the present study was to determine the role of SOCS-2 in the regulation of bone mineral density (BMD). Dual x-ray absorptiometry (DXA) analyses demonstrated that the areal BMD of the tibia was reduced in both 4-wk-old (-8.6%) and 15-wk-old (-6.0%) SOCS 2-/- mice compared with wild-type (WT) mice. The trabecular volumetric BMD, as measured by peripheral quantitative computerized tomography (pQCT) in the metaphyseal region of the distal femur, was reduced in both 4-wk-old (-10%) and 15-wk-old (-32%) SOCS 2-/- mice compared with WT mice. pQCT analyses in the diaphyseal region of tibia also revealed that the cortical volumetric BMD was reduced in both 4-wk-old (-7%) and 15-wk-old (-3%) SOCS 2-/- mice. The cortical cross-sectional area was reduced in 4-wk-old but not in 15-wk-old SOCS 2-/- mice. In conclusion, SOCS-2 inactivation results in reduced trabecular and cortical volumetric BMD. These effects are not consistent with an augmented GH/IGF-I signaling and, therefore, the mechanism behind the reduced BMD remains to be elucidated.