The response to continuous intravenous infusion of levodopa was evaluated in 23 patients with Parkinson's disease complicated by motor fluctuations. Conversion from oral to intravenous levodopa treatment resulted in an immediate and sustained stabilization of plasma levodopa levels in both the wearing-off and on-off groups. Motor variability also diminished within the first 24 hours of infusion, although to a much greater extent in patients with the wearing-off phenomenon. Over the next 5 to 11 days of intravenous treatment, further reductions in motor fluctuations occurred in both groups, at a substantially faster rate in the wearing-off group than in the on-off group. The degree of immediate stabilization of parkinsonian motor response correlated best with disease duration, whereas the rate of subsequent improvement correlated most closely with levodopa dose. The results support the view that the wearing-off phenomenon may reflect the degeneration of dopamine terminals as a consequence of natural disease progression with a resultant inability to buffer variations in levodopa availability; the on-off phenomenon may reflect additional postsynaptic changes, possibly occurring in response to the nonphysiological fluctuations in synaptic dopamine, which gradually remit during continuous levodopa administration.