The purpose of the present study was to determine the effect of acute administration of insulin-like growth factor I (IGF-I) or insulin on in vivo protein synthesis in muscle and other organs in fasted mice and to compare this response with that produced by feeding. Recombinant IGF-I (3.3 nmol prime, 3.33 nmol/h) or insulin (0.056 nmol/h) was infused intravenously for 60 min along with glucose to prevent hypoglycemia. Fractional rates of tissue protein synthesis (FSR) were determined by injection of [2H5]phenylalanine (25 mg/100 g body wt, 40% enriched). Both IGF-I and insulin caused a 25% increase in FSR of heart (P < 0.001) and soleus muscle (P < 0. 05) and a 65% increase in gastrocnemius and plantaris muscle (both P < 0.001), thus restoring rates to those seen in fed animals. A fivefold lower dose of IGF-I also stimulated protein synthesis in gastrocnemius muscle and heart (both P < 0.05) but not in soleus muscle. No significant effects of IGF-I on FSR were detected in liver, kidney, spleen, proximal small intestine, colon, lung, or brain. The results indicate that the ability of an overnight fast to decrease protein synthesis and the acute effects of insulin and IGF-I to stimulate protein synthesis are restricted to skeletal and cardiac muscles.