The contribution of central pharmacodynamic mechanisms to the pathogenesis of motor fluctuations in advanced Parkinson's disease was studied in 29 patients by evaluating their acute response to intravenously injected levodopa. While the threshold dose for an antiparkinsonian effect did not change, that for induction of dyskinesia showed a progressive reduction in 4 groups: (1) levodopa-naive patients, (2) those with a stable response to oral administration, and (3) those with wearing-off or (4) on-off fluctuations. Concomitantly, the therapeutic window for levodopa narrowed and the levodopa dose-antiparkinsonian response slope increased. The antiparkinsonian threshold dose correlated best with duration of symptoms; the dyskinesia threshold dose, therapeutic window, and dose-response slope related most closely with the duration of levodopa treatment. The differing dose-response profiles for the antiparkinsonian and dyskinetic effects suggest involvement of separate pharmacological mechanisms. The present results, taken together with previous observations that the wearing-off phenomenon responds promptly to plasma levodopa stabilization while on-off fluctuations tend to diminish over several days, suggest that postsynaptic modifications, presumably at the receptor level, serve as the major determinant for the increasing difficulty with optimal dose adjustment and the motor fluctuations, especially of the on-off type, which complicate levodopa therapy of patients with advanced Parkinson's disease.