OBJECTIVES: This study compared the costs in claims associated with fibromyalgia plus depression, fibromyalgia alone, and depression alone. METHODS: Using administrative claims data from a national Fortune 100 manufacturer, 3 mutually exclusive cohorts and an overall beneficiary cohort were defined based on diagnostic claims: fibromyalgia-only, depression-only, fibromyalgia plus depression, and a random sample comprising 10% of the employer's overall beneficiary sample. The cohorts were compared for demographics, comorbid conditions, health care resources used, medication use by therapeutic class, and mean direct costs and imputed indirect costs. RESULTS: Mean annual costs per patient to the employer were $5,163 for fibromyalgia-only, $8,073 for depression-only, $11,899 for fibromyalgia plus depression, and $2,486 for patients in the overall sample. Mean incremental employer costs (above overall sample payments) per patient for those with fibromyalgia plus depression were a cost addition of $1,149 when compared with the sum of the incremental costs for those with fibromyalgia-only and depression-only ((11,899-2,486)-(5,163-2,486)+(8,073-2,486)). For every dollar spent on fibromyalgia healthcare costs for employees (medical care plus prescriptions), the employer spent $57 to $143 on additional direct and indirect costs. CONCLUSIONS: Patients with both fibromyalgia and depression claims are high users of the health care system. Although data are limited to an insured population, they concur with previous literature establishing relationships between depression and painful conditions. When fibromyalgia and depression co-occur there is more than additive relationship between the incremental costs versus single syndrome cohorts. Improved management of these patients could result in reduced patient, physician and employer burdens.