OBJECTIVES: We evaluated the effectiveness of traditional disease-modifying antirheumatic drugs (tDMARDs) and novel DMARDs, alone and in combination, in methotrexate- and biologic-naive adults with moderate to severe early rheumatoid arthritis (ERA; <3-year duration). METHODS: Literature review identified randomized controlled trials (RCTs) of tDMARDs and novel DMARDs reporting efficacy outcomes (American College of Rheumatology [ACR] 20/50/70/90 response and Disease Activity Score at 28 joints [DAS28] remission). Data were pooled using Bayesian network meta-analysis techniques. For ACR response, data were analyzed using a fixed-effects ordered probit model, which makes efficient use of ordered categorical data and guarantees coherent prediction of multinomial response probabilities. For DAS28 remission, data were analyzed with a fixed-effects binomial logit model. Sensitivity analyses tested the effects of grouping treatments by class and broadening/narrowing inclusion criteria. RESULTS: Results from a synthesis of 16 RCTs of tDMARDs (methotrexate, sulfasalazine, hydroxychloroquine) and novel DMARDs (biologics [abatacept, adalimumab, etanercept, infliximab, golimumab, tocilizumab] and tofacitinib) indicated that biologics+methotrexate, triple tDMARDs, and tocilizumab and tofacitinib monotherapy significantly increased response across all ACR categories versus methotrexate. ACR response probabilities for biologics+methotrexate were not significantly different between agents. ACR response probabilities to novel DMARD monotherapy varied, trending toward higher values for tofacitinib and tocilizumab than etanercept or adalimumab. In studies reporting DAS28 remission, treatment with tofacitinib or biologics±methotrexate, except adalimumab alone, improved remission likelihood versus methotrexate. Tocilizumab±methotrexate generated the highest probability of remission among biologics and was significantly more effective than other biologics±methotrexate and tofacitinib. Results across outcomes were robust to alternative grouping of interventions and change in inclusion criteria. CONCLUSIONS: Based on ACR response, the expected efficacy of biologics+methotrexate, tofacitinib and tocilizumab monotherapy, and triple tDMARD therapy appeared higher than MTX in ERA. Tocilizumab±methotrexate was expected to have the highest probability of generating DAS28 remission and was significantly more effective than other biologics±methotrexate and tofacitinib.