In clinical trials, etanercept has been shown to improve health outcomes and functional status. This observational study was undertaken to evaluate etanercept in a non-trial (naturalistic) setting. OBJECTIVE: To analyze the impact of etanercept on HRQOL and functional status in persons with RA in a naturalistic setting. METHODS: 1043 persons with RA and on etanercept therapy were followed in an observational, longitudinal study. HRQOL and functional status data was obtained via mailed questionnaires at baseline and at 6 months. Vitality and mental health was measured by domain questions on the Medical Outcomes Study Short Form 36 (SF-36). Functional outcomes were measured by the Health Assessment Questionnaire (HAQ). RESULTS: 82.3% of the sample were women. The mean age was 54 years. Both the SF-36 vitality and mental health domain scores had clinically meaningful improvements. The mean score at baseline for vitality was 30.3 units (0-100, 100=no impairment) and mental health was 58.0 units. At 6 months, vitality improved by 20.5 units and mental health improved by 13.4 units. 70.6% of the sample for vitality and 53.3% for mental health experienced clinically meaningful improvements of at least 10 units at 6 months. The mean HAQ index at baseline was 1.54 units (0-3, 3=greatest disability). At 6 months follow-up, the mean index decreased (improved) by 0.68 units. At the 6 month follow-up, 77.9% of the sample experienced a clinically meaningful improvement in HAQ index of 0.25 units or greater. Additionally, 10.6% achieved a zero HAQ index and 36.9% achieved an index of 0.5 units or less. CONCLUSION: In this naturalistic study, etanercept demonstrated significant improvement in HRQOL and functionality, as measured by the SF-36 and HAQ.