Importance: Restless legs syndrome (RLS) is a neurological disorder characterized by unpleasant sensations in the legs and a distressing, irresistible urge to move them. We conducted a systematic review to evaluate efficacy, safety, and comparative effectiveness of pharmacologic treatments for primary RLS. Evidence Acquisition: We included randomized controlled trials (RCTs), published in English, reporting efficacy outcomes and harms of pharmacologic treatments for primary RLS of at least 4 weeks' duration. MEDLINE and other databases were searched through June 2012. Reviewers extracted outcomes and adverse events and rated the strength of evidence. Results: We identified 29 eligible RCTs. We found highstrength evidence that the proportion of patients who had a clinically important response (International Restless Legs Syndrome [IRLS] responders), defined as a 50% or greater reduction from baseline in mean IRLS symptom scale scores, was greater with dopamine agonist therapy compared with placebo (61% vs 41% ) (risk ratio, 1.60 [95% CI, 1.38-1.86]; 7 trials). Dopamine agonists also improved patient-reported sleep scale scores and qualityof- life measures. High-strength evidence demonstrated that calcium channel alpha-2-delta ligands increased the proportion of IRLS responders compared with placebo (61% vs 37%) (risk ratio, 1.66 [95% CI, 1.33-2.09]; 3 trials). Adverse events associated with dopamine agonists included nausea, vomiting, and somnolence. Alpha- 2-delta ligands adverse events included somnolence and unsteadiness or dizziness. Conclusions and Relevance: On the basis of shortterm RCTs that enrolled highly selected populations with long-term high-moderate to very severe symptoms, dopamine agonists and calcium channel alpha-2-delta ligands reduced RLS symptoms and improved sleep outcomes and disease-specific quality of life. Adverse effects and treatment withdrawals due to adverse effects were common.