OBJECTIVES:   To examine the effect of medication choice between duloxetine and pregabalin on medication compliance outcomes as well as direct healthcare costs among patients with fibromyalgia. METHODS: A retrospective cohort study design was used with a large US national commercial healthcare claims database over 2005-2007. Fibromyalgia patients aged 18-64 who initiated (no pill coverage in the previous 90 days) duloxetine or pregabalin in 2006 were selected, with the first initiation date as the index date. All patients included had continuous enrollment in the 12 months pre- and post-index periods. Patients with diabetic peripheral neuropathic pain (DPNP) or depression in the 12 months pre-index period were excluded. Each patient was classified in the duloxetine or prebagalin cohort based on the initial agent. Prebagalin cohort was constructed via propensity scoring controlling for differences in demographics, pre-index clinical and economic characteristics, and pre-index treatment patterns. Medication compliance (i.e. medication possession ratio (MPR) and proportion of patients with MPR≥80%) and healthcare costs over the 12 months post-index period were examined between cohorts. RESULTS: Both the duloxetine (n = 3711) and pregabalin (n=4111) cohorts had the mean age around 50 years. Many duloxetine and pregabalin patients had neuropathic pain other than DPNP (69.1% vs. 69.1%), low back pain (61.9% vs. 62.1%), cardiovascular disease (55.1% vs. 55.1%), hypertension (44.9% vs. 45.0%), and headache (36.0% vs. 35.3%), and used opioids (75% vs. 86%). Controlling for demographics, pre-index clinical and economic characteristics, and prior medication history, duloxetine patients had significantly higher MPR (0.66 vs. 0.50, p<0.05), higher proportion of patients with MPR≥80% (47% vs. 26%, p<0.05), and significantly lower total healthcare costs ($19,378 vs. $27,045, p<0.05) over the 12 months follow-up period than pregabalin patients. CONCLUSIONS: Fibromyalgia patients treated with duloxetine had significantly higher medication compliance, but significantly lower direct healthcare costs than those on pregabalin.