The treatment of homocystinuria that is not responsive to pyridoxine is not usually biochemically or clinically successful, and vascular, ocular, and skeletal complications commonly supervene. Persistent marked homocysteinemia appears to be the most important biochemical disturbance leading to these complications. Ten patients with cystathionine beta-synthase deficiency that was not responsive to pyridoxine and one patient with homocystinuria due to a defect in cobalamin metabolism were treated with 6 g daily of betaine added to conventional therapy, to improve homocysteine remethylation. All patients had a substantial decrease in plasma total homocysteine levels (P less than 0.001) and an increase in total cysteine levels (P less than 0.001). Changes in plasma methionine concentrations were variable. Fasting levels of plasma amino acids became normal in two patients, and in six there was immediate clinical improvement. There were no unwanted effects. We conclude that treatment of homocystinuria that is not responsive to pyridoxine and of disorders of homocysteine remethylation should include betaine in adequate doses to ensure maximum lowering of elevated plasma homocysteine levels.