OBJECTIVES: Target measures such as DAS-28 < 2.6 are the goal of treatment in rheumatoid arthritis (RA). In general, DAS-28<2.6  is associated with improved functionality and reduced resource use but with higher treatment  costs. This study evaluated whether treatment strategies that were more effective but more expensive in achieving DAS-28<2.6 in moderate to severe RA patients were cost effective (CE). METHODS: A micro-simulation model of 10,000 RA patients was developed that estimated lifetime Health Assessment Questionnaire (HAQ) progression, quality adjusted life years (QALYs) and direct costs from a UK NHS perspective.  The model incorporated an initial response criterion of achieving a DAS-28  <2.6 at 6 months after initiating treatment that triggered treatment switching to subsequent therapies upon failure. Scenario 1 compared a treatment sequence of a high efficacy biologic therapy followed by conventional DMARD therapy versus a less efficacious biologic therapy followed by a cDMARD. Scenario 2 compared two multiple biologic treatment sequences with a difference in efficacy between the first biologic in each sequence .  A sensitivity analysis and a CE efficiency frontier analysis examined the effect of varying the difference in  DAS-28 < 2.6  rates (ΔRem) between first-line therapies. RESULTS: In scenario 1, a ΔRem of 10% between the bDMARDs yielded a mean per-patient gain of 0.117 QALYs and a mean per-patient increase in total cost £2,590, giving an incremental cost-effectiveness ratio (ICER) of £22,112 per QALY.  In scenario 2, the higher efficacy bDMARD strategy had an ICER of £6,720 when ΔRem =10%. CONCLUSIONS: Over a lifetime, treating to the target of DAS-28< 2.6  with more efficacious therapies in  RA patients was cost-effective at various levels of efficacy differences . The higher costs of longer term treatment were offset by the increased quality of life for patients with DAS-28 < 2.6 as well as reduced hospitalisation costs.