The effects of insulin on glucose utilization, lipolysis, and potassium and phosphate metabolism were studied during short-term fasting in six lean subjects using a sequential euglycemic glucose clamp technique (two additional subjects were used in 70 mU/m²/min clamp studies). The subjects were infused with insulin for four hours at four rates ranging from 6 to 442 mU/m²/min before and after a 48-hour fast. Insulin was infused for one hour at each rate in all experiments. Fasting markedly reduced glucose utilization at all insulin infusion rates. On the other hand, the decline in levels of free fatty acids that occurred at insulin concentrations of 30 μU/ml was virtually identical before and after fasting. After insulin was infused for four hours, serum phosphate had decreased in all subjects (P < 0.001) and strongly correlated with glucose disposal rates (r = 0.76, P < 0.005). The plasma potassium level also declined in all subjects but did not relate to fasting or glucose disposal. These studies demonstrate that starvation produces selective insulin resistance. The biologic effect of insulin on glucose utilization and plasma phosphate shifts is clearly diminished. Free fatty acid and potassium metabolism are unaffected by starvation.