Plasma tryptophan (Trp) levels and brain concentrations of Trp, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) were measured in chronically uremic rats fed either 11% or 18% casein diets for 8 to 12 weeks. Uremic rats had increased levels of plasma urea nitrogen and 5-HIAA when compared with sham-operated pair-fed controls. The level of plasma total Trp decreased in both uremic groups and the level of plasma free Trp increased only in those fed an 11% casein diet. Uremic rats fed 11% casein had a higher level of plasma free Trp than those fed 18% casein. The ratio of plasma total Trp to the sum of five amino acids competing for the blood-brain transport system was decreased in both uremic groups, and the ratio of plasma free Trp to the same amino acids was increased only in uremic rats fed 11% casein. The concentration of brain 5-HIAA increased in uremic rats fed 11% casein, and that of Trp and serotonin decreased in uremic rats fed 18% casein. These results indicate that uremic stress and changes in protein intake in chronic uremia alter plasma Trp levels and brain serotonin metabolism.