Objectives: To evaluate the prevention of knee joint destruction and clinical efficacy of methotrexate (MTX) plus etanercept (ETN) compared with MTX monotherapy in patients with rheumatoid arthritis (RA) by using semi-automated software for magnetic resonance imaging (MRI) scan analysis. Materials and methods: This study enrolled patients with active moderate-to-severe RA who displayed an inadequate response to oral MTX at screening. Patients were assigned to receive either MTX plus ETN or MTX monotherapy (≥10 mg/week). The primary endpoint was the quantitative knee cartilage volume using our software developed for MRI scan analysis. Results: A total of 18 female patients were enrolled in this study and allocated to the MTX + ETN group (n = 9) or the MTX monotherapy group (n = 9). At 52 weeks, the quantitative knee cartilage volume was significantly reduced compared with baseline in both groups (MTX plus ETN group: 2.3 ± 2.3 cm3; MTX monotherapy group: 2.4 ± 1.6 cm3); however, the difference was not significant. Conclusion: The semi-automated software for MRI scan analysis can reveal useful and potentially clinically important information about the characteristics of knee joint destruction in patients with RA.