Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the most frequent cause of death for SSc but there is still no sufficient treatment available. Although cyclophosphamide (CYC) therapy is a common treatment which has shown statistical efficacy against SSc-ILD to date, its effects are temporary and not enough. Rituximab (RTX), the anti-CD20 monoclonal antibody, has recently shown efficacy in many autoimmune diseases. In SSc-ILD, RTX is also considered to be one of the novel treatment candidates. However, studies of SSc-ILD in Japanese treated with RTX have only a few case reports. Therefore, in this study, we retrospectively compared nine patients treated with RTX and 30 patients treated with CYC to investigate the efficacy of RTX treatment for Japanese anti-topoisomerase I-positive SSc-ILD patients. At the 24-month evaluation, the improvement rates of percent predicted of forced vital capacity and percent predicted of diffusing capacity of the lung carbon monoxide in the RTX-treated group were significantly higher than those in the CYC-treated group (20.6 ± 8.8% vs 1.1 ± 3.9%; P < 0.05 and 34.0 ± 6.0% vs -1.5 ± 2.8%; P < 0.01, respectively). In addition, skin thickness scores also showed a marked improvement from 13.5 points before the start of treatment to 5.8 points after 24 months by RTX therapy (P < 0.05). These results suggest that RTX treatment is more effective for Japanese SSc-ILD patients than CYC treatment. In the future, it is expected that large-scale clinical trials will show the usefulness of RTX treatment for SSc-ILD.