Eighteen depressed outpatients were treated for 6 wk with amitriptyline. Clinical improvement was monitored using the Hamilton Depression Rating Scale administered by two psychiatrists blind to the tricyclic used for treatment, dosage, and plasma levels. Amitriptyline and its desmethyl metabolite, nortriptyline, were assayed twice weekly by gas chromatography-mass fragmentography. For the 17 patients having total tricyclic plasma levels between 0 and 250 ng/ml, there was a negative correlation between the Hamilton score and the mean total tricyclic level (p < 0.01) and amitriptyline level (p < 0.005). The mean nortriptyline level did not significantly correlate with the Hamilton score. The 10 patients having mean total tricyclic levels above 95 ng/ml had lower median Hamilton scores at week 3 (p < 0.025) and at week 6 (p < 0.0025) than those whose tricyclics were lower. The percentage of recovered patients increases significantly as the plasma levels rise to 250 ng/ml, the maximum plasma level considered in this study.