Hyperlipidemia has been reported in adults with hypopituitarism, and human (h) GH therapy has been shown to lower plasma cholesterol in patients with hypercholesterolemia. Macrophage cholesterol accumulation is an early event in atherosclerosis, and these cells have been shown to respond to GH and insulin-like growth factor (IGF-I). The present study was aimed at investigating the activity of GH and IGF-I in macrophages, and used murine macrophages as a model system to investigate the effects of GH and IGF-I on cellular uptake and metabolism of low density lipoprotein (LDL). The J-774 murine macrophage cell line was shown to bind hGH, to respond to hGH by an increase in cell IGF-I content, and to have specific high affinity binding sites for IGF-I. Mouse peritoneal macrophages and the J-774 macrophage cell line respond to hGH with a dose-dependent stimulation of cellular association and degradation of LDL as well as an enhanced cholesterol esterification rate. A similar response was observed after in vitro treatment of the cells with IGF-I. Preliminary results in human monocyte-derived macrophages showed similar results. The dependency of the effect of hGH on locally produced IGF-I was shown by abrogation of the hGH effect after adding anti-IGF-I antibody to the culture medium. It is concluded that murine macrophages possess the machinery to bind GH, produce IGF-I, and bind IGF-I. This machinery is used by macrophages, and apparently by other cells, to execute GH-dependent IGF-I-mediated stimulation of cellular uptake and metabolism of LDL. This may provide the explanation for both the elevated plasma LDL concentration in patients with GH deficiency and the effect of GH therapy to reduce plasma LDL levels.