Serum from GH-treated hypophysectomized rats was examined by two-dimensional gel electrophoresis followed by silver staining to screen a large number of serum proteins for GH responsiveness. A distinctive, highly acidic protein of 60,000 mol wt was clearly responsive to GH administration, increasing 7-fold over levels observed in hypophysectomized controls. Administration of T4, corticosterone, and 5α-dihydrotestosterone failed to induce this protein; however, addition of GH to this regimen resulted in a 60-fold increase in its concentration. Examination of proteins synthesized by isolated hepatocytes in the presence of [35S]methionine showed that this protein is of hepatic origin. Physiological and physiochemical evidence suggest that this protein is unlikely to be one of the other well documented GH-responsive serum proteins: somatomedin-C, α2U-globulin, or the somatomedin-binding protein. The protein demonstrates a remarkable ontogeny, increasing 135-fold over newborn levels by 35 days of age. This is qualitatively similar to changes observed in somatomedin-C, however, the quantitative change is much more striking. Examination of the protein in an altered physiological state which limits growth (uremia) reveals a 30-fold diminution of levels of the protein after 3 weeks of renal failure. In contrast, pair-fed animals demonstrated only a 2-fold decrease. This suggests that there is a profound inhibition of GH action which is not accounted for by poor nutritional intake. This protein may be useful in the investigation of the GH-hepatic axis.