Background: Rasagiline mesylate is a novel drug for Parkinson’s disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinson’s disease and motor fluctuations. Methods: In an 18-week, double-blind, multicentre (74 hospitals and academic centres in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline (231 individuals; 1 mg once daily), entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary outcome was change in total daily off-time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinson’s disease rating scale (UPDRS) scores. Analysis was by intention to treat. Findings: 88 (13%)patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n=34) and adverse events (n=34). Both rasagiline and entacapone reduced mean daily off-time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4h; p=0.0001, p < 0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p=0.0005 for both). We recorded significant mean improvements in CGI scores (-0.86 rasagiline and -0.72 entacapone vs -0.37 placebo; p < 0.0001, p=0.0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (-1.71 and -1.38 vs placebo; p < 0.0001, p=0.0006, respectively) and motor function during on-time (-2.94 and -2.73 vs placebo; both p < 0.0001). Frequency of adverse events was similar for all treatments. Interpretation: Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson’s disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone. Background: Rasagiline mesylate is a novel drug for Parkinson’s disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinson’s disease (231 individuals; 1 mg once daily) and motor fluctuations. Methods: In an 18-week, double-blind, multicentre (74 hospitals and academic centers in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline , entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary measures was change in total daily off-time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinson’s disease rating scale (UPDRS) scores. Analysis was by intention to treat. Findings: 88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), main Both rasagiline and entacapone reduced mean daily off-time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4 h; p = 0.0001, p <0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p = 0.0005 for both). We recorded significant mean improvements in CGI scores (-0.86 rasagiline and -0.72 entacapone vs -0.37 placebo ; p <0.0001, p = 0.0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (-1.71 and -1.38 vs placebo; p < both on-time (-2.94 and -2.73 vs placebo; both p <0.0001). Interpretation: Once-daily rasagiline reduces mean daily off-time and improvement symptoms of Parkinson’s disease in levodopa- treated patients with motor fluctuations, an effect similar to that of entacapone.