SOCS2-deficient (SOCS2^-/-) mice grow significantly larger than their littermates, suggesting that SOCS2 is important in the negative regulation of GH and/or IGF-I actions. The aim of this study was to identify genes and metabolic parameters that might contribute to the SOCS2^-/- phenotype. We demonstrate that although SOCS2 deficiency induces significant changes in hepatic gene expression, only a fraction of these overlap with known GH-induced effects in the liver, suggesting that SOCS2 might be an important regulator of other growth factors and cytokines acting on the liver. However, an important role of GH and IGF-I in the phenotype of these animals was demonstrated by an over-expression of IGFBP3 mRNA in the liver and increased levels of circulating IGFBP3 protein. Other GH-like effects included diminished serum triglycerides and down-regulation of lipoprotein lipase in adipose tissue. Interestingly, SOCS2^-/- mice did not differ from their wild-type littermates in glucose or insulin tolerance tests, which is in contrast to the known diabetogenic effects of GH. Furthermore, there was no evidence of impaired insulin signaling in primary hepatocytes isolated from SOCS2^-/- mice. Moreover, increased expression of PGC-1 mRNA was detected in skeletal muscle, which might contribute to a normal glycemic control despite the apparent overactivity of the GH/IGF-I axis. Our data indicate that SOCS2 deficiency partially mimics a state of increased GH activity but also results in changes that cannot be related to known GH effects.