Objective: To determine whether the apolipoprotein E4 (Apo E4) allele may be a genetic risk factor for fibromyalgia syndrome (FMS). Design: A retrospective assessment of associations between Apo E4 genotype and selected environmental exposures among a cohort diagnosed with FMS compared with control subjects. Setting: Marshfield Clinic Research Foundation's Personalized Medicine Research Project (PMRP) biobank. Participants: One hundred fifty-one case subjects with fibromyalgia and 300 age- and gender-matched control subjects. Methods: Fibromyalgia case subjects were identified according to a strict phenotypic definition from among the nearly 20,000 subjects enrolled in the PMRP. Age- and gender-matched control subjects also were identified from the PMRP in a 2:1 control/case ratio. Apo E4 genotype was determined by single nucleotide polymorphism analysis for both case subjects with fibromyalgia and control subjects. Case subjects with fibromyalgia and control subjects were asked to assess their level of function and stress by completing the Short Form-36 and the Perceived Stress Scale. Main Outcome Measures: Statistical associations between the Apo E4 genotype and phenotypic criteria (diagnosis of FMS) as well as historical environmental exposures as documented in the electronic medical record were assessed. Results: Approximately one quarter of both case subjects with fibromyalgia and control subjects were found to carry at least one Apo E4 allele. The odds ratio (OR) for case subjects with fibromyalgia who had ever been in a motor vehicle accident and subsequently had been diagnosed with FMS was increased among those with at least one copy of the Apo E4 allele (OR 7.04) compared with those without an Apo E4 allele (OR 1.90). The presence of an Apo E4 allele did not influence the degree of pain or level of function among those with FMS. Conclusions: These data suggest that specific interactions between genetically susceptible individuals (eg, those with at least one copy of the Apo E4 allele) and the environment (eg, involvement in a motor vehicle accident) may contribute to the risk of being diagnosed with FMS, although Apo E4 allele status does not appear to modulate perceived FMS severity.