OBJECTIVES: To assess effects of etanercept therapy on vitality using the Health Assessment Questionnaire (HAQ).   METHODS: Eighty-nine patients with moderate to severe rheumatoid arthritis (RA) were randomized in a phase 2/3 study to evaluate efficacy/safety of 25 mg etanercept twice weekly given in combination with methotrexate. Fifty-nine patients were randomized to etanercept/methotrexate and 30 to placebo/methotrexate. The HAQ was administered at baseline, Days 8/15, and every 4 weeks from Weeks 4−24. Vitality was assessed using 4 items: Feel full of pep? Feel worn out? Have enough energy to do the things you want to do? Feel tired? Patients responded on a 5-point scale ranging from All the time to Never. Using standard scoring algorithms, the vitality score ranged from 0 (worst) to 100 (best). Anchor and distribution-based methods were employed to estimate the minimally important difference (MID) for improvement. A repeated measures model was used to compare change from baseline over time between groups. RESULTS: At baseline, mean vitality scores were 34 with 95% confidence interval (CI) of 30 to 39 for etanercept/methotrexate patients versus 40 (95% CI 33 to 47) for placebo/methotrexate patients. At Week 24, the unadjusted mean improvements in vitality scores from baseline were 22 (95% CI 17 to 28) for etanercept/methotrexate versus 8 (95% CI 2 to 15) for placebo/methotrexate patients. The MID was established at 9.0, and 37% etanercept/methotrexate patients achieved the MID at Day 8 versus 17% placebo/methotrexate patients. The percentage rose to 67% versus 42% at Week 12, and to 74% versus 38% at Week 24 for etanercept/methotrexate versus placebo/methotrexate patients, respectively.  The repeated measures model indicated a statistically significant difference in vitality change from baseline over time between the treatments (P = 0.025). CONCLUSIONS: The vitality MID was achieved by 74% of patients on etanercept/methotrexate by Week 24 versus 38% on placebo/methotrexate.