Twelve parkinsonian patients with levodopa-related end-of-dose fluctuations in disability were studied in an open-label trial to examine the effects of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on pharmacokinetics and metabolism of levodopa and on clinical response to levodopa after a single dose and after 4 weeks' medication with entacapone. The clinical response was assessed with continuous monitoring using the motor part of Unified Parkinson's Disease Rating Scale. Entacapone increased statistically significantly the mean area under the plasma concentration-time curve (AUC) of levodopa by 29% after a single dose and by 21% after 4 weeks' administration, without affecting other pharmacokinetic parameters of levodopa. The AUC of 3-O-methyldopa decreased by 45% and AUC of homovanillic acid by 21% after 4 weeks' dosing with entacapone. The duration of motor response to levodopa increased significantly from 2.3 h to 3.2 h (i.e., by 39%) after a single dose and to 3.4 h (i.e., by 48%) after 4 weeks' medication with entacapone. The magnitude of clinical response remained unchanged, but peak latency of motor response was prolonged after 4 weeks' medication. The duration and magnitude of dyskinesias also increased. Peripheral COMT inhibition with entacapone increased significantly the bioavailability of levodopa and prolonged its antiparkinsonian effect after a single dose and after repeated dosing for 4 weeks. Thus entacapone seems to be a valuable adjuvant to levodopa treatment in parkinsonian patients with end-of-dose failure.