To determine if the molecular form of nitrogen intake affects protein metabolism during feeding, 12 normal volunteers received, by continuous nasogastric infusion, a protein or a peptide-based diet. Leucine kinetics (oral [13C]leucine and intravenous [2H3]leucine) were measured during the following three consecutive periods: first carbohydrates and lipids alone, then with either whole casein or oligopeptides in a randomized crossover design, with these two latter periods being isonitrogenous, isocaloric, and of identical amino acid compositions. Leucine concentration, turnover, oxidation, and nonoxidative disposal increased during nitrogen administration (all P < 0.01) and were higher with oligopeptides than with casein (242 +/- 44 vs. 188 +/- 31 mumol/l; 2.75 +/- 0.45 vs. 2.23 +/- 0.31; 1.14 +/- 0.19 vs. 0.82 +/- 0.22 mumol.kg-1.min-1, all P < 0.001; 1.64 +/- 0.32 vs. 1.44 +/- 0.33 mumol.kg-1.min-1, P < 0.05, respectively). Endogenous leucine production was less inhibited by oligopeptides than by casein (0.82 +/- 0.41 vs. 0.38 +/- 0.31 mumol.kg-1.min-1, P < 0.001), whereas splanchnic extractions were similar. Finally, leucine balance was more positive with casein than with oligopeptides (P < 0.001). In conclusion, the response of leucine kinetics to feeding is modified by the molecular form of nitrogen intake, with the oligopeptides inducing a higher oxidation and protein synthesis and a lesser inhibition of protein breakdown.