OBJECTIVES: To systematically review the current cost-effectiveness literature of biological disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis and to explore reasons for differences in results. METHODS: Medline, Embase, BIOSIS, Derwent Drug File, Cochrane library and NHS-EED were searched on 12th March 2007 for studies published from 2002-2007. Full economic analyses of bDMARDs were included after a two-stage review process. Bibliographies of included studies were searched for additional citations. RESULTS: Nine hundred and nine unique citations were retrieved, and 18 studies met our criteria. Six analyses were carried out in the UK, 5 in the US, 4 in Sweden, 2 in Canada and 1 in the Netherlands and Japan. One of the 18 studies included both UK and Swedish analyses. Nine studies assessed the cost-effectiveness of at least 2 bDMARDs, including etanercept, infliximab, adalimumab and anakinra; while the other 9 compared a single bDMARD with standard DMARDs (e.g. methotrexate, MTX). Three studies compared the cost-effectiveness of infliximab plus MTX versus MTX alone, and 6 estimated the cost-effectiveness of etanercept compared with standard DMARDs. Decision modelling was used in 16 studies. The 3 analyses that compared infliximab plus MTX with MTX alone (2 based on the same decision model) provided similar results within acceptable thresholds for willingness-to-pay (Incremental Cost-Effectiveness Ratio [ICER] £35,000, €50,000 or $50,000/QALY). Contrasting results were, however, found in the etanercept studies. In 3 cases, etanercept-MTX combination was found to be a cost-effective strategy compared to other DMARDs (generally MTX alone). In the other 3 economic evaluations, etanercept (as monotherapy or in combination with MTX) was not cost-effective compared to standard DMARDs. CONCLUSION: The review found a preponderance of cost-effectiveness analyses. Differences in etanercept results appear be due to differences in model structure and underlying modelling assumptions. This finding is consistent with a recent review of infliximab cost-effectiveness analyses.