OBJECTIVES: The clinical benefit of initial combination therapy with infliximab in patients with rheumatoird arthritis was established in BeSt, a randomized clinical trial assessing the impact of four treatment strategies in patients recently (less than 2 years) diagnosed with RA. Treatment options were sequential monotherapy with DMARDs (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with infliximab (group 4). The cost-effectiveness of initial combination therapy with infliximab vs. sequential DMARD monotherapy was evaluated. METHODS: Data on clinical outcomes (Health Assessment Questionnaire [HAQ]) were extracted from the two-year publication of BeSt and extrapolated to five years.  Medical resource use and drug costs (2006 £) were obtained from the British National Formulary and two systematic NICE reviews of TNF-α inhibitors in RA.. Model outcomes, from a UK payer perspective, included cost per one-point improvement in HAQ and cost per quality-adjusted life-year (QALY); cost and benefit were discounted at 3.5%. HAQ scores were translated into QALYs using an established algorithm. Probabilistic sensitivity analyses were conducted to determine the impact of drug cost, HAQ improvement, and translation between HAQ and QALY. RESULTS: Initial combination therapy with prednisone or infliximab led to earlier HAQ improvement vs. sequential monotherapy and step-up combination therapy. Cumulative costs in group 1 increased from £1,155 to £15,875; costs in group 4 rose from £8,131 to £22,155. QALYs improved more in group 4 (0.70 to 3.30) than in group 1 (0.62 to 2.91). Cost per QALY declined from £92,764 (year 1) to £15,965 (year 5) for initial combination therapy with infliximab vs. sequential monotherapy. Results were not sensitive to changes in drug cost, HAQ, or the conversion algorithm. CONCLUSIONS: Higher costs associated with the earlier use of infliximab are offset by this regimen’s clinical benefit over time.