The primary defect in patients presenting with a history of protein intolerance, mental retardation, and epilepsy of variable degree, with the unique triad of hyperornithinemia, hyperammonemia, and homocitrullinuria (the HHH syndrome) has been postulated to be a defect in translocation of ornithine into the mitochondria. In a 12-year-old boy with the HHH syndrome, the hyperammonemia observed following a protein load was prevented when the same load was given orally with a 1 mmol/kg of ornithine-HCl. At a dosage level of 0.5 to 1.0 mmol/kg/day of ornithine HCl, administered in 3 divided doses with meals, the patient's protein tolerance improved. As pretreatment hyperammonemia reverted to normal levels, the patient was able to cope with increased dietary protein and his growth accelerated. During the 2-year interval of the study, the ornithine HCl supplements were withdrawn on 2 occasions, and within a week the hyperammonemia recurred. Whereas cultured fibroblasts from the HHH patient were capable of oxidizing U-14C-glutamate to 14CO2 as rapidly as normal cells. 1-14C-ornithine or 5-14C-ornithine were oxidized at only 1/28 or 1/49 of the normal rate. Ultrastructural studies of the HHH cultured fibroblast mitochondria revealed distinctive alterations in size and shape; unusually long, branching, and "curling," HHH mitochondria also showed accelerated regressive changes.