OBJECTIVES: To compare, in the absence of head-to-head trials, the clinical benefit of gabapentin enacarbil, levodopa, pramipexole, ropinirole, and rotigotine in the treatment of moderate-to-severe restless legs syndrome (RLS). METHODS: A mixed treatment comparison (MTC) was performed using the Bayesian approach in the software WinBUGS. A systematic literature review was first conducted to identify RLS trials published over the past ten years through search on MEDLINE, EMBASE, Cochrane CENTRAL and manufacturers’ websites. Twenty-eight clinical trials were retained after two screenings. To minimize heterogeneity on dosing and trial duration, a smaller set of fifteen trials were included in the primary analysis, comprising 4,413 patients. A sensitivity analysis was then performed on the full set of twenty-eight trials to validate the results of the primary analysis. RESULTS: The indirect comparison was established among four active treatments (gabapentin enacarbil, pramipexole, ropinirole, rotigotine) and placebo, due to the lack of latest clinical evidence on levodopa. Analysis on the primary endpoints indicates that rotigotine is most likely to lead to the greatest reduction in IRLS score from baseline (probability of 64.7% at the end of maintenance, and of 70.6% at week 12). Rotigotine’s comparative therapeutic benefit is also observed in IRLS responders rate and in five out of six items of the RLS-6 scale. CONCLUSIONS: Based on the results of this MTC, rotigotine is most likely the most efficacious treatment option to alleviate RLS symptoms. Head-to-head clinical trials should be conducted to confirm the findings of this MTC.