OBJECTIVE: To study the effect of entacapone, a specific peripherally acting catechol-O-methyltransferase (COMT) inhibitor used in combination with levodopa treatment, in cases of Parkinson's disease with both fluctuating and non-fluctuating response to treatment. METHODS: A randomised, placebo controlled, double blind, six month study was undertaken in 172 fluctuating and 128 non-fluctuating patients. The clinical efficacy and safety of 200 mg entacapone given with each daily levodopa dose was studied. Efficacy was examined using home diaries, the unified Parkinson disease rating scale (UPDRS), and recording of daily levodopa dose. RESULTS: The primary efficacy variable for fluctuating patients-the proportion of daily ON time-showed a significant increase compared with placebo (p <0.05). The absolute ON time (mean (SD)) increased from 9.5 (2.5) to 10.8 (2.4) hours (p <0.01), and the daily OFF time was correspondingly reduced from 7.0 (2.6) to 5.9 (2.5) hours (p <0.05 v placebo). This improvement was achieved despite a reduction in daily levodopa requirements. The effect was rapidly lost on withdrawal of entacapone. In non-fluctuating patients, the primary efficacy measure was part II of the UPDRS (activities of daily living; ADL). In this group of patients, ADL scores improved in the entacapone group (p <0.01 v placebo), and there was also a 40 mg reduction in levodopa requirement (p <0.01 v placebo). Entacapone was well tolerated by both fluctuating and non-fluctuating patients. CONCLUSIONS: The ability of entacapone to provide additional benefits to levodopa treatment in increasing ON time in fluctuating Parkinson's disease patients was confirmed. A novel finding was that patients without fluctuations also obtained benefit from the addition of entacapone to their levodopa treatment, as evidenced by improved ADL scores and a relatively reduced levodopa requirement.