Two brothers previously diagnosed as having alpha-aminoadipic aciduria (alpha-AA) were subjected to a tryptophan loading test to determine if their condition resulted from a defect in the alpha-aminoadipate aminotransferase (kynurenine aminotransferase) system. Normal increases in kynurenic and xanthurenic acids eliminated this possibility. Further analyses of their urines revealed that both boys had measurable amounts of previously undetected alpha-ketoadipic acid (alpha-KA) before and after the loading test. A reexamination of speciments from a prelysine and postlysine loading test reconfirmed the existence of alpha-KA in their urines at the time the original observation of alpha-AA was made. The response to the lysine load was a predictable increase in both alpha-AA and alpha-KA. The boy who had been referred to this institution with a learning defect responded to the tryptophan load with a slight decrease in alpha-AA and an unpredicted decrease in alpha-KA and 3-hydroxykynurenine. His mentally normal brother showed a significant decrease in alpha-AA and major increases in all other measured metabolites including alpha-KA. The latter results were compatible with a defect in the oxidative decarobxylation of alpha-KA. A comparison of the urinary alpha-AA and alpha-KA concentrations in our subjects with comparable data in mentally normal and mentally retarded patients with this condition suggested that the retardation may result from other causes.