OBJECTIVES Fibromyalgia is a chronic condition characterized by widespread pain and decreased physical function. This study compares the economic burden in patients diagnosed with Fibromyalgia (FM) with that of patients diagnosed with Chronic Fatigue Syndrome (CFS) and patients with Major Depressive Disorder and other Depressive Disorders (DEP). METHODS Claims data were obtained from the Thomson/Medstat MarketScan Commercial Claims Database. Study subjects aged 18+ with continuous eligibility were required to have ≥1 inpatient claim or ≥2 outpatient claims during 2006 with ICD-9-CM codes for one of the disease conditions. Patient groups were not mutually exclusive (1.0% of FM patients had CFS and 10.8% had DEP). Mean annual third-party payer costs/patient were calculated based on paid claims. Incremental costs relative to FM were generated using generalized linear models (family=gamma, link=log), adjusting for age, gender, beneficiary status, employment status, insurance plan type, comorbid prevalence of FM, DEP, CFS, and other comorbidities. RESULTS A total of 77,124 FM, 11,672 CFS and 215,380 DEP patients met all study entry criteria. Total unadjusted costs for FM patients ($10,187) were similar to that of DEP patients ($10,416) and greater than CFS patients ($8,314). The highest unadjusted cost category for all patients were outpatient costs (FM $5594; DEP $4972; CFS $4605), followed by inpatient costs (FM $2367; DEP $3136; CFS $2067). Prescription costs (FM $2226; DEP $2308, CFS $1641) were the lowest cost category. After adjusting for covariates, third-party payer costs for FM patients were not significantly different than costs for CFS patients and were 9% ($984) lower costs for DEP patients. CONCLUSIONS The costs to treat FM patients are high and comparable to that for CFS and DEP, other chronic diseases with similar symptoms and/or often covered by third-party payers. Early diagnosis and use of effective treatments for FM could reduce the economic burden on third-party payers.