Raised plasma free fatty acid (FFA) levels effectively impede glucose uptake in vivo, thereby conserving plasma glucose and sparing glycogen. To test whether FFA have any effect on blood amino acid levels, we infused Intralipid plus heparin or saline into healthy volunteers under four different experimental conditions: A) overnight fast; B) euglycemic hyperinsulinemia (approximately 100 microU/ml); C) hyperglycemic (approximately 200 mg/100 ml) hyperinsulinemia (approximately 50 microU/ml); and D) hyperglycemic (approximately 300 mg/100 ml) normoinsulinemia (approximately 20 microU/ml). In the fasting state (A), lipid infusion was associated with lower blood levels of most amino acids, both branched chain and glucogenic. This effect, however, could not be ascribed to lipid infusion alone, because plasma insulin levels were also stimulated. The clamp studies (B, C, and D) allowed to assess the influence of lipid on blood amino acid levels at similar plasma insulin and glucose levels. It was thus observed that lipid infusion has a significant hypoaminoacidemic effect of its own under both euglycemic (B) and hyperglycemic (C) conditions; this effect involved many glucogenic amino acids (alanine, glycine, phenylalanine, serine, threonine, and cystine) but none of the branched-chain amino acids (leucine, isoleucine, and valine). In marked contrast, normoinsulinemic hyperglycemia (D), with or without lipid infusion, caused no change in the blood level of any measured amino acid. We conclude that lipid infusion has a hypoaminoacidemic action. We also suggest that this action is permitted by insulin and may involve specific metabolic interactions (e.g., reduced availability of glucose-derived pyruvate or glycerophosphate) as well as enhanced uptake by the liver.