BACKGROUND: Sarcopenia has been attributed to a diminished muscle protein synthetic response to food intake. Differences in digestion and absorption kinetics of dietary protein, its amino acid composition, or both have been suggested to modulate postprandial muscle protein accretion. OBJECTIVE: The objective was to compare protein digestion and absorption kinetics and subsequent postprandial muscle protein accretion after ingestion of whey, casein, and casein hydrolysate in healthy older adults. DESIGN: A total of 48 older men aged 74 +/- 1 y (mean +/- SEM) were randomly assigned to ingest a meal-like amount (20 g) of intrinsically l-[1-(13)C]phenylalanine-labeled whey, casein, or casein hydrolysate. Protein ingestion was combined with continuous intravenous l-[ring-(2)H(5)]phenylalanine infusion to assess in vivo digestion and absorption kinetics of dietary protein. Postprandial mixed muscle protein fractional synthetic rates (FSRs) were calculated from the ingested tracer. RESULTS: The peak appearance rate of dietary protein-derived phenylalanine in the circulation was greater with whey and casein hydrolysate than with casein (P < 0.05). FSR values were higher after whey (0.15 +/- 0.02%/h) than after casein (0.08 +/- 0.01%/h; P < 0.01) and casein hydrolysate (0.10 +/- 0.01%/h; P < 0.05) ingestion. A strong positive correlation (r = 0.66, P < 0.01) was observed between peak plasma leucine concentrations and postprandial FSR values. CONCLUSIONS: Whey protein stimulates postprandial muscle protein accretion more effectively than do casein and casein hydrolysate in older men. This effect is attributed to a combination of whey's faster digestion and absorption kinetics and higher leucine content. This trial was registered at clinicaltrials.gov as NCT00557388.