OBJECTIVE: To examine the cost-effectiveness of ropinirole for the treatment of primary restless legs syndrome (RLS) versus the alternative off-label therapies of pramipexole and pergolide. METHODS: A cost-effectiveness analysis was conducted from the societal perspective using a cohort of 10,000 United States adults 45 years old and older with moderate-to-severe primary RLS. A decision tree was used to model cost-effectiveness for a two-year period following commencement of dopamine agonist therapy. Outcome probabilities were obtained from a systematic review of randomized controlled trials and observational studies. Costs were derived from standard 2005 health care cost references. Cost-effectiveness decision models were created for base-case analyses. One-way and probabilistic sensitivity analyses were conducted to test the robustness of the findings. RESULTS: In terms of changes in the International Restless Legs Syndrome Study Group Rating Scale (IRLS) score for RLS severity, pergolide dominates ropinirole given the base-case. Pergolide is cost-saving when compared to both ropinirole and pramipexole, resulting in a saving of $1687 and $556 per one-point improvement in IRLS score. One-way sensitivity analyses indicated that the IRLS scores for augmentation strongly influenced the calculated incremental cost effectiveness ratios (ICERs). Probabilistic sensitivity analyses revealed variation in the results indicating a lack of clear dominance. CONCLUSIONS: None of the therapies is clearly dominant in terms of cost per IRLS score change. Although ropinirole is currently the only U.S. Food and Drug Administration (FDA) approved medication for the treatment of RLS, it is not more cost-effective than alternate off-label dopamine agonists prescribed for RLS.