OBJECTIVES: To assess the ability of adalimumab + MTX to improve health-related quality of life (HRQOL) in early RA and interpret the results. METHODS: PREMIER was a 2-year study of MTX-naïve, adult patients with early RA (<3 years) who received: adalimumab 40 mg every other week (eow) + MTX; adalimumab 40 mg eow; or MTX monotherapy. The Short Form 36 (SF-36) was used to assess 8 domains of HRQOL at baseline, and after 12, 26, 42, 52, 76, and 104 weeks of therapy (higher scores indicate improvement). Scores for 4 physical and 4 mental health concepts were aggregated into Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. A minimum clinically important difference (MCID) is 2.5–5.0 for PCS and MCS. Criteria-based interpretation of the PCS evaluated relationships between clinically and socially meaningful variables. RESULTS: Baseline scores for the 799 patients were comparable between all 3 groups, and post-baseline results were comparable for the 2 monotherapy groups. Mean baseline PCS for the adalimumab + MTX (n=256) and MTX monotherapy (n=247) groups were 31.7 and 32.2. Mean PCS for the combination therapy group at Week 12 had improved to 42.2 vs. 38.2 for the MTX group. The 4.5 difference in mean change from baseline was clinically meaningful and sustained through 2 years (5.1) (p<0.0001). Based on criteria-based interpretation of the SF-36, differences in PCS scores between the 2 groups indicate patients on MTX alone had an increased likelihood of using more health resources and not being able to work. CONCLUSIONS: Adalimumab + MTX was superior to MTX alone in providing significant and clinically meaningful improvements in HRQOL in early RA. Significantly lower PCS at 2 years in the MTX group may mean patients on MTX alone have greater health care utilization and substantially greater job loss than patients on combination therapy.