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Objective: To assess the clinical efficacy of a novel once-daily extended-release (ER) formulation of the dopamine agonist pramipexole as monotherapy in patients with early Parkinson disease (PD) and establish its noninferiority vs standard immediate-release (IR) pramipexole. Methods: This was a multicenter, double-blind, parallel study of patients with early PD not receiving levodopa or dopamine agonists, randomly assigned to pramipexole IR, pramipexole ER, or placebo. Seven-week flexible titration was followed by 26-week maintenance, with levodopa permitted as rescue medication. The primary analysis was to test pramipexole ER noninferiority to pramipexole IR based on a change in the Unified Parkinson9s Disease Rating Scale (UPDRS) part II+III score at 33 weeks, with noninferiority predefined as a treatment group difference for which the lower bound of the 95% confidence interval (CI) did not exceed −3 points. Results: Among 213 ER and 207 IR recipients, the adjusted mean 33-week UPDRS II+III change (excluding levodopa rescue effects) was −8.2 for ER and −8.7 for IR, a difference of −0.5 with a 95% CI of −2.3 to 1.3. Compared with placebo (n = 103), pramipexole ER and pramipexole IR were significantly superior on UPDRS II+III score, all key secondary outcomes, and almost all other endpoints. On the 39-item Parkinson Disease Questionnaire, superiority of pramipexole ER failed to reach statistical significance. Both formulations were equally safe and well-tolerated. Conclusions: As monotherapy for early PD, pramipexole ER was noninferior to pramipexole IR and significantly more effective than placebo. Tolerability and safety did not differ between the formulations. Classification of evidence: This study provides Class I evidence that pramipexole ER is not inferior to pramipexole IR in patients with early PD. Neurology ® 2011;77:759–766