To synthesize evidence from available randomized controlled trials (RCT) to compare the efficacies of dopaminergic drugs (pramipexole, ropinirole and rotigotine) and α-2-δ ligands (gabapentin enacarbil and pregabalin) for the treatment of restless legs syndrome (RLS). We searched PubMed for all eligible RCTs. Network meta-analysis using frequentist methodology with random effect models was performed for mean changes in scores on the International RLS Study Group Rating Scale (IRLS) and for responder rates on Clinical Global Impressions-Improvement (CGI-I); analyzed as odds ratio (OR). Network meta-analysis of mean changes in IRLS data from 35 studies with 7333 participants showed that all treatments, in specific gabapentin enacarbil, followed by pregabalin and rotigotine were superior to placebo [mean reduction in IRLS scores: -5.31 (-6.74 to -3.87), -5.20 (-6.91 to -3.49), 5.17 (3.73-6.61), respectively] but there were no significant differences between active treatments. Network meta-analysis of 5137 participants from 24 studies showed that gabapentin enacarbil and rotigotine were associated with the highest CGI-I response rates [ORs: 5.68; (95% CI, 4.14-7.21); and 4.68 (2.87-6.49), compared to placebo, respectively]. No significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropinirole. Based on IRLS scores and CGI-I response rates, while gabapentin enacarbil, pregabalin and rotigotine stand out as the most efficacious of all examined drugs, it is noteworthy that no significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropiniriole (for CGI-I response rates).