This present study was designed to examine (1) whether a combination therapy of TNF (tumor necrosis factor) blockers and methotrexate (MTX) is better than MTX monotherapy, and (2) if the TNF inhibitors such as etanercept, infliximab and adalimumab are all same for treating patients with active rheumatoid arthritis (RA). We performed meta-analysis of a combination therapy of TNF-blockers and MTX compared to MTX monotherapy and we performed adjusted indirect comparison of the TNF-blocking agents for their efficacy and toxicity. Three studies met the inclusion criteria for the analysis. Meta-analysis showed that the combination of MTX with anti-TNF inhibitors was more effective than MTX monotherapy and this indicated that combination therapy of anti-TNF inhibitors and MTX was comparable with MTX monotherapy in terms of withdrawal due to the side effects (RR: 1.05, 95% CI: 0.52-2.09, P = 0.86). The adjusted indirect comparison did not show any differences between infliximab and adalimumab. However, there was a significant difference for clinical efficacy and side effects between etanercept, adalimumab and infliximab. The RRs for achieving ACR20, ACR50 and ACR70 responses and withdrawal due to the side effect in the etanercept group were lower when compared with the adalimumab group. The RR for achieving an ACR20 response in the etanercept group was lower when compared with the infliximab group. The adjusted indirect comparison analysis suggests that the TNF-blocking agents all are not the same with respect to effectiveness and toxicity for the treatment of active RA.