Acute tryptophan depletion (ATD) induces transient clinical relapse in medicated patients with major affective disorder. Our objective was to determine whether this effect persists once patients are euthymic and off antidepressants. Thus, we examined the effects of ATD in fully remitted, medication-free, former patients with major depression (n = 14). ATD had no significant effect on mood. These results suggest that the previous report that ATD substantially lowers mood in pharmacologically treated patients reflects a reversal of mechanisms involved in the therapeutic effects of antidepressants. Alternatively, ATD might induce clinical relapse only in subgroups that have yet to be identified.