Growth hormone (GH) and insulin-like growth factor I (IGF-I) selectively increase tissue mass. We compared the fractional rate of protein synthesis (K-s) in skeletal muscle, jejunal mucosa and muscularis, and liver to investigate the differential effects of GH and IGF-I on tissue protein synthesis. Surgically stressed rats were maintained with hypocaloric total parenteral nutrition (TPN) and given recombinant human (rh) GH (rhGH), rhIGF-I, rhGH + rhIGF-I (800 or 800 + 800 mu g/day, respectively), or TPN alone. After 3 days, a flooding dose of valine (800 mu mol with 5.56 MBq L-[3,4-H-3]valine) was administered, and rats were killed 20 min later. Body weight gain, nitrogen retention, and serum IGF-I concentrations confirmed that GH plus IGF-I additively increased anabolism, Serum insulin concentrations were significantly increased by GH and decreased by IGF-I. GH significantly increased K-s in skeletal muscle and jejunal muscularis, IGF-I significantly increased K-s in jejunal mucosa and muscularis, and neither GH nor IGF-I altered K-s in liver. GH and IGE-I differentially increase tissue protein synthesis in vivo.