Methylmalonicaciduria is an inborn error of metabolism characterized by protein intolerance, neonatal or infantile ketoacidosis, long chain ketonuria, and by the accumulation of large amounts of methylmalonic acid (MMA) in blood and urine. The present study examines the metabolic basis for these features in a young boy with the vitamin B12-dependent variant of this disorder. A diet containing 5 gm of protein per kg body weight per day resulted in transient ketoacidosis, long chain ketonuria, and increased methylmalonicaciduria. Isoleucine, valine, methionine, and threonine, all known MMA precursors, were responsible for this protein intolerance. Oral loads of each of these amino acids resulted in equimolar 1,000 µg increases in urinary MMA. Valine and isoleucine also precipitated mild ketoacidosis and long chain ketonuria. Injections of vitamin B12 (1000 µg per day) promptly lowered urine MMA by 70% and partially corrected the defect in propionate or methylmalonate oxidation found in the patient's leucocytes or platelets. While receiving vitamin B12, the clinical toxicity of a valine load was abolished and its biochemical effects significantly modified. These findings demonstrate that the observed protein intolerance and ketoacidosis in patients with methylmalonicaciduria are direct results of the primary block in methylmalonate catabolism and that vitamin B12 acts by overcoming, in part, this metabolic block. These conclusions imply that children with this disorder should respond to dietary protein restriction and/or vitamin B12 supplementation, a regimen on which our patient has thrived for over 2 years.