Interactions between the 5-HT system and the dopaminergic system and cholinergic system may be important in determining cognitive function and motor function in Parkinson's disease (PD). Previous studies have shown effects of reducing serotonin function, by acute tryptophan depletion (ATD), on neuropsychological function. In particular, an adverse effect on verbal memory has been demonstrated. This study compared with the effects of ATD on cognitive and motor function in PD and healthy control subjects. The effects of ATD were investigated in a double-blind, placebo-controlled, counterbalanced, cross-over, randomised design in 20 patients with PD and 35 healthy controls matched for age, gender and premorbid IQ. There was a differential group effect of ATD on global cognitive function whereby the mean score on the modified mini mental state examination during ATD was lower than placebo in PD but higher in controls. There was a similar pattern of effects on verbal recognition. In a visual recognition task, ATD improved performance in the PD but not in the control group. In terms of psychomotor speed, there was also a group-specific effect with reduced latency of response during ATD in the PD group but increased latency in the control group. ATD has subtle neuropsychological effects, which differ significantly between PD and healthy control subjects. This suggests that the dopaminergic and cholinergic deficit of PD significantly modulates the effects of serotonin depletion, resulting in positive effects in some domains. Further investigation on the effects of specific serotonin antagonists may be merited in PD.