Background: Motor response fluctuations and dyskinesias compromise long-term levodopa therapy in Parkinson’s disease. Variations in plasma levodopa levels contribute to adverse reactions associated with chronic therapy. Therefore, sustained-release levodopa preparations may be associated with less motor fluctuations and a better outcome. We conducted a large, 5-year, multicenter study to address this hypothesis. Methods: Six hundred and eighteen nonfluctuating patients with Parkinson’s disease never exposed to levodopa therapy were randomized to (Sinemet® CR 50/200) sustained-release or immediate-release (Sinemet® 25/100) carbidopa/levodopa preparations in 35 centers worldwide. Dosage titration occurred over the 5 years of evaluations to maintain an optimal response. The primary endpoint, the ‘event’, was the presence of motor fluctuations, as defined by 20% ‘off time or 10% ‘on’ time with dyskinesias as recorded in the patient diary, or greater than or equal to a 50% positive response on the physician fluctuations questionnaire. Clinical rating scales, Nottingham Health Profile (NHP) and adverse reactions were also recorded. Findings: During the 5 years of the study, both treatment groups responded extremely well to therapy. The incidence of all patients reaching the ‘event’ was low, approximately 20% by diary criteria and 16% by questionnaire definition, and there was no significant difference between the two treatment groups. Activities of daily living scores in the Unified Parkinson Disease Rating Scale (UPDRS) consistently favored the Sinemet CR treatment group and a number of the NHP scales also favored the CR group. Based upon the frequency of adverse experiences, and the overall low incidence of withdrawals, the two treatment groups demonstrated very similar safety profiles. The most common drug-related effect was nausea; seen in 20% of patients. Other drug-related effects were dizziness, insomnia, abdominal pain, dyskinesia, headache and depression. Drug-related withdrawals were less than 10% of all patients, primarily due to nervous/psychiatric complaints. Interpretation: During a 5-year treatment period, control of parkinsonian symptoms was maintained by both immediate-release and sustained-release carbidopa/levodopa. Both treatment regimens were associated with a low incidence of motor fluctuations and dyskinesias. There was a statistically significant difference (p < 0.05) in activities of daily living as measured by the UPDRS in favor of Sinemet CR.