Cognitive processing is associated with deactivation of the default mode network. The presence of dopaminoceptive neurons in proximity to the medial prefrontal node of this network suggests that this neurotransmitter may modulate deactivation in this region. We therefore used positron emission tomography to measure cerebral blood flow in 15 Parkinson's disease (PD) patients while they performed a motor sequence learning task and a simple movement task. Scanning was conducted before and during intravenous levodopa infusion; the pace and extent of movement was controlled across tasks and treatment conditions. In normal and unmedicated PD patients, learning-related deactivation was present in the ventromedial prefrontal cortex (p < 0.001). This response was absent in the treated condition. Treatment-mediated changes in deactivation correlated with baseline performance (p < 0.002) and with the val(158)met catechol-O-methyltransferase genotype. Our findings suggest that dopamine can influence prefrontal deactivation during learning, and that these changes are linked to baseline performance and genotype.