Since human immunoglobulins exert an insulinlike stimulatory effect on adipocyte lipogenesis at concentrations markedly lower than those found in vivo, and since human serum or plasma are only mildly stimulatory, we predicted that human serum probably contains an inhibitor of adipocyte lipogenesis. Supernatant preparations, obtained from the precipitation of immunoglobulins from plasma in 2.5 mol/1 ammonium sulphate, were extensively dialysed and tested for their activity on bioassay systems commonly used for measuring insulin. The supernatants produced a marked inhibition of basal and insulin-or IgG-stimulated lipogenesis and glucose oxidation by adipocytes at protein concentrations of 10 rag/1. The supernatants were further purified through ul-trafiltration to demonstrate two main inhibitory fractions, 10 to 30 K and 30 to 50 K, which again produced marked inhibition of basal and insulin-or IgG-stimulated adipocyte lipogenesis and glucose oxidation. These fractions were then tested for basal and serum somatomedin-stimulated 35S sulphate uptake by porcine cartilage: both basal and serum somatomedin-stimulated 35S uptake were significantly inhibited (p < 0.01). Therefore, normal human serum contains at least two peptides which are markedly inhibitory to glucose metabolism and insulin action on adipocytes and 35S transport and somatomedin action on cartilage.