The effect of levodopa on L-[11C]DOPA influx rate was evaluated in patients with early and advanced Parkinson's disease (PD) by using positron emission tomography (PET). The patients were scanned both drug-free and after a subsequent therapeutic levodopa infusion. Regional analysis of striatal L-[11C]DOPA influx rate showed a correlation to the degenerative loss of nerve terminals reported at postmortem analysis in PD. Levodopa induced markedly differential effects on the striatal L-[11C]DOPA influx rate in early and advanced patients. In patients with mild PD, levodopa infusion decreased L-[11C]DOPA influx, whereas in patients with advanced PD, levodopa induced significant upregulation of L-[11C]DOPA influx. These changes were confined to the putamen and were, in both patient categories, most prominent in the dorsal part of the region. The present investigation demonstrates a marked shift in the modulatory action of levodopa with the advancement of PD and suggests the induction of positive feedback in advanced PD. These findings could help explain the less graded clinical response to levodopa in advanced PD and would thus have importance for the understanding of the pathogenesis underlying motor fluctuations.