We tested the relative ability of rapidly digested whey and slowly digested casein to stimulate net whole-body protein synthesis during prolonged physical inactivity. We studied 8 young male volunteers after they consumed isonitrogenous casein or whey mixed meals on d 12 or d 14 of experimental bed rest. Rates of phenylalanine hydroxylation were measured by primed-constant oral administration of L[2-(2)H(2)]tyrosine and L[ring-(2)H(5)]phenylalanine for 3 h in the postabsorptive state and 6 h after an isonitrogenous bolus meal containing sucrose (0.27 g/kg) and casein or whey (0.40 g/kg). Net protein synthesis in the fed state was calculated during the first 6 h postmeal as the difference between phenylalanine hydroxylation and phenylalanine content in the ingested casein or whey. In the fed state, the integrated changes in phenylalanine hydroxylation were lower (P < 0.05) after whey (-2 +/- 8 micromol x kg(-1) x 6 h(-1)) than after casein ingestion (34 +/- 7 micromol x kg(-1) x 6 h(-1)). During bed rest, net postprandial protein synthesis was greater (P < 0.05) after whey (96 +/- 8 micromol phenylalanine x kg(-1) x 6 h(-1)) than after casein ingestion (82 +/- 7 micromol phenylalanine x kg(-1) x 6 h(-1)). The rapidly digested whey protein was more efficient than the slowly digested casein in increasing postprandial net protein synthesis during short-term bed rest.