We used [11C]raclopride (RACLO) and positron emission tomography (PET) to study longitudinally striatal dopamine D2 receptor binding in nine patients with Parkinson's disease (PD) at an early drug-naive stage and 3–5 years later, when motor fluctuations had appeared in seven of them. Patients were treated with a combination of levodopa and dopamine agonists. Data were compared with 10 healthy controls in the same age range. Initially, patients with PD showed a significant increase of RACLO uptake in the putamen compared with controls (p < 0.04). The caudate nucleus revealed values in the normal range. After 3–5 years, RACLO binding was significantly reduced in the putamen (p < 0.03) and caudate nucleus (p < 0.03) compared with baseline. Values were now in the control range in the putamen and reduced in the caudate nucleus (p < 0.05). The clinical score at “off” had significantly worsened (p < 0.0005) compared with the first PET scan. The nine PD patients reported here had already been investigated 3–4 months after therapy began and at that time did not show a reduction of the initially increased RACLO binding capacity (data published previously). These results indicate long-term downregulation of striatal dopamine D2 receptor binding in PD. Receptor changes in the striatum of patients with PD may be induced by chronic dopaminergic therapy or occur independently of treatment, as a result of structural adaptation of the postsynaptic dopaminergic system to the progressive decline of nigrostriatal neurons.