Reduced serotonergic tone may be a compensatory adaptation to reduced dopaminergic activity in Parkinson's disease (PD) and may result in vulnerability to depression. To test this hypothesis this study examined the effects of serotonin depletion, using the technique of acute tryptophan depletion (ATD) in PD. The effects of ATD were investigated in a double-blind, placebo-controlled, counterbalanced, cross-over, randomised design, in 20 patients with PD and 32 healthy controls matched for age, gender and pre-morbid IQ. The primary outcome was change in scores on a modified Montgomery-Asberg Depression Rating Scale (MADRS). ATD resulted in a small but statistically significant increase in score on the MADRS, but there was no effect specific to the PD group. The results do not support the hypothesis that low serotonergic tone results in vulnerability to depression in PD and are in accord with an earlier study using the same technique in PD.