Previous research provides evidence linking serotonin (5-hydroxytryptamine, 5-HT) with stress and depression. The controllable/uncontrollable (C/UC) stress paradigm aims to generate a state/condition, namely a feeling of lack of control in the context of a stressor, which might be an important factor in precipitating a negative mood state. Acute tryptophan depletion (ATD) is a technique that produces a decrease in central 5-HT levels in vivo. This study investigated the role of 5-HT in the behavioral response to a C/UC stress paradigm with ATD. Healthy adult volunteers were randomly assigned to receive either a TRP-supplemented (n = 15) or TRP-deficient (n = 13) amino acid drink. At 5 hours postdrink, volunteers were subjected to sessions of controllable and uncontrollable noise stress (100-dB white noise). Subjective ratings of mood were obtained before and after the interventions. Participants who received the tryptophan-depleting drink had greater self-report ratings of negative mood on visual analogue scales and the Profile of Mood States after the uncontrollable stress than did participants who received the balanced drink. The results suggest that 5-HT might play a role in providing resilience to uncontrollable stress. Additional studies with specific 5-HT pharmacologic probes will further clarify the results.