We treated 65 outpatients with RDC major depression in a randomized, prospective, double-blind comparison of oral L-tyrosine, 100 mg/kg/day, imipramine, 2.5 mg/kg/day, or placebo for 4 weeks. Tyrosine increased and imipramine decreased 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion significantly, but there was no evidence that tyrosine had antidepressant activity. The only side effect to achieve statistical significance was greater dry mouth with imipramine. MHPG excretion and plasma amino acid concentrations failed to predict or correlate with clinical improvement.