BACKGROUND: Deficiencies in brain serotonin function are believed to play an important role in the pathophysiology of seasonal affective disorder/winter type (SAD). However, no direct evidence has been reported so far that lowered brain serotonin activity causes the symptoms of SAD. METHODS: We studied 11 SAD patients who had suffered recurrent winter depressive episodes of SAD and were fully recovered and off treatment during the summer. In a randomized, balanced, double-blind crossover design patients received two amino acid beverages, one containing tryptophan and the other containing no tryptophan but otherwise identical. Behavioural ratings and plasma total and free tryptophan concentrations were assessed at baseline before administration of the amino acid beverages and at several time points afterwards. RESULTS: The tryptophan-free amino acid beverage induced significant decreases of plasma total and free tryptophan levels and both levels increased during sham depletion (condition x time interaction: P < 0.001). Tryptophan depletion, but not sham depletion caused a transient return of depressive symptoms (condition x time interaction: P < 0.001). CONCLUSIONS: The present study demonstrates that SAD patients in remission during the summer are vulnerable to a return of depression when depleted of tryptophan. This finding supports the importance of serotonergic mechanisms in the pathophysiology of SAD.