OBJECTIVES: To evaluate the cost-effectiveness of duloxetine for the management of fibromyalgia assessed from the perspective of a health care payer in the United States. METHODS: A Markov model was used to evaluate the economic and clinical advantages in controlling fibromyalgia pain symptoms, considering duloxetine as an additional treatment option. The standard treatment sequence was defined based on clinical guidelines including tricyclic antidepressants (TCAs), second-generation antidepressants (based on SNRIs), anticonvulsants, and opioid therapies. The model included 2 levels of pain response (a ≥30% and ≥50% change from baseline, using a standard 11-point severity scale). Clinical efficacy and discontinuation data were taken from a systematic literature review and mixed treatment comparison, including both placebo and active controlled trials. Utility data were linked to pain severity using trial-based EQ5D data. Discounting was applied at 3.0% per year. RESULTS: The introduction of duloxetine resulted in additional symptom-controlled months (SCMs), defined as the amount of time at a ≥30% response level, and quality-adjusted life years (QALYs), over a 2-year time horizon. First-line treatment resulted in an additional 665 SCMs and 12.3 QALYs, with a cost of $582,911 ($877 per SCM and $47,560 per QALY). Second-line treatment resulted in an additional 460 SCMs and 8.7 QALYs, with a cost of $143,752 ($312 per SMC and $16,565 per QALY). A cost-effectiveness frontier analysis suggested that second-line duloxetine is likely to be the most cost-effective option, however, in sensitivity analyses, the cost-effectiveness of first-line duloxetine improved when assumptions around continued treatment switching for long-term drop-outs were relaxed. CONCLUSIONS: There is currently a significant unmet need for patients with poorly controlled fibromyalgia where pain is a predominant symptom. These analyses show that the introduction of duloxetine into the standard treatment sequence for fibromyalgia can provide additional patient benefits, which are cost-effective when compared to commonly adopted thresholds.