Passage of amino acids across the blood-brain barrier is assumed to be modified by amino acid composition of the blood. To gain a better understanding of the effects of protein intake on brain amino acid uptake, we examined associations among diet, plasma amino acid patterns, and the rate of entry of valine into the brain. Rats were fed (8 h/day for 7-10 days) diets containing 6, 18, or 50% casein before receiving one meal of a diet containing 0, 6, 18, or 50% casein. After 4-7 h, they were anesthetized and infused intravenously with [14C]valine for 5 min before plasma and brain samples were taken for determination of radioactivity and content of individual amino acids. As protein content of the meal was increased from 0 to 50% casein, plasma and brain concentrations of valine and most other large neutral amino acids (LNAA) increased severalfold; also the ratio of [14C]valine in brain to that in plasma decreased by greater than 50%, and the rate of valine entry into the brain increased 3.5-fold. The increase in valine flux slowed as plasma levels of LNAA, competitors for valine transport, increased. The results were far more dependent on protein content of the final meal than on that of the adaptation diet; thus changes in protein intake, as reflected in altered plasma amino acid patterns, markedly altered valine entry into the brain.