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Background: Acute tryptophan depletion (ATD) induces depressive symptoms in remitted depressed patients treated with serotonergic medications, but not in patients treated with noradrenergic medications or electroconvulsive therapy. A recent study suggests that cognitive therapy (CT) protects against the effects of ATD, but the evidence is questionable. The present study compared the effect of ATD in patients who were treated with antidepressant medication and CT (n = 17) versus antidepressant medication alone (n = 23) during their latest episode. Methods: Forty remitted depressed patients underwent high-dose and low-dose ATD in a randomized double-blind crossover design. Results: There were no differences in response to ATD between treatment groups. This applied to groups defined by lifetime and by recent CT experience. Conclusions: Cognitive therapy does not protect against the effects of rapidly lowered plasma tryptophan levels in remitted depressed patients who are also treated with antidepressant medication. [Copyright &y& Elsevier]