In a double-blind study of 24 patients with endogenous depressiona group treated with clomipramine hydrochloride (chlorimipramine) plus tryptophan was compared with a group treated with clomipramine plus placebo. The sum of the ratings for depressed mood, suicidal intent, depressive thought content, and anxiety showed a more rapid improvement in the former group, the difference being already significant after 12 days of treatment. On the other hand, the ratings for retardation decreased about equally in both groups during the three-week treatment period. Side-effect ratings showed no significant increase but seemed to be partly influenced by the improvement of depressive symptoms. Plasma levels of clomipramine appeared to reach a plateau within a few days, whereas the monodesmethylated metabolite continued to rise for a longer period of time, and reached considerably higher values than the parent compound. In the tryptophan group the degree of improvement seemed to be positively correlated to these levels, suggesting that further improvement might have been reached in some patients by increasing the dose of clomipramine. The levels of 5-hydroxyindoleacetic acid in the cerebrospinal fluid appeared to be reduced by clomipramine administration. This effect was prevented by the additional treatment with tryptophan.