Objective We examined whether infliximab (IFX) therapy was more effective than methotrexate (MTX) monotherapy to achieve an improvement in depressive states in Rheumatoid Arthritis (RA) patients. Methods We examined 152 RA patients (72 IFX patients and 80 MTX patients). We conducted an open-label cohort study to evaluate the disease activity of RA (Simplified Disease Activity Index; SDAI), depressive states (Hamilton Rating Scale for Depression; HAM-D), Activity of Daily Living (ADL) (modified Health Assessment Questionnaire; mHAQ) and Quality of Life (QOL) [Short Form (SF)-36] in patients before and 6 months after receiving therapy. The HAM-D, SDAI, mHAQ and SF-36 scores after 6 months of therapy were measured as the outcomes. Results We analyzed 60 IFX patients and 53 MTX patients. The HAM-D scores significantly improved in both groups (p<0.001), but there was no significant difference in the effectiveness between the IFX and MTX therapies (p=0.792). The SDAI scores significantly improved in both groups after therapy (p<0.001), and IFX therapy was more effective than MTX therapy (p=0.004). The mHAQ and HAM-D scores also improved significantly in both groups after therapy (p<0.001), but no significant difference in the effectiveness between the IFX and MTX therapies was observed (p=0.272, 0.792). The scores of all 8 items of the SF-36 improved in both groups after therapy, but IFX therapy was more effective than MTX therapy in only 4 of the 8 items (p<0.05). Conclusion Both IFX and MTX therapy improved the clinical efficacy, ADL, QOL and depressive states. However, no significant differences regarding an improvement in the depressive states and ADL were observed between IFX therapy and MTX monotherapy.