Impaired gastric emptying may be the cause for some response fluctuations in Parkinson's disease (PD), especially the “delayed-on” and “no-on” phenomena. Cisapride is a prokinetic drug that enhances gastric emptying by releasing acetylcholine from the myenteric plexus. Tolerability and safety as well as efficacy of cisapride was studied in an open-label trial on 15 fluctuating PD patients. Twelve patients had “delayed-on” and six had “no-on” phenomena. They filled out daily diaries on times of levodopa intake and of turning “on” and “off” for 1 week on levodopa alone and for an additional week of pretreatment with cisapride, 30 min before early morning, early afternoon, and late evening doses of levodopa. Cisapride significantly shortened latency to “on” from 60 ± 20 to 45 ± 19 min after the morning dose and from 63 ± 17 to 47 ± 22 min after the evening doses. Patients with “no-on” phenomenon had a decreased number of dose failures from 23 before to nine during cisapride treatment. The drug was well tolerated, with no important side effects. Our study supports the role of impaired gastric emptying in some subtypes of motor fluctuations and indicates that they may be improved by prokinetic drugs.