OBJECTIVES: The RESOLVE-1 trial of lenabasum in diffuse cutaneous systemic sclerosis (dcSSc) allowed background immunosuppressive therapy (IST) at the discretion of individual investigators, and no significant differences were observed between treatment arms. This provides a powerful opportunity to compare the relative efficacy of different ISTs in a well-defined large cohort of patients with dcSSc. METHODS: Prespecified IST categories, efficacy end points, baseline disease characteristics likely to influence efficacy outcomes, the definition of interstitial lung disease, definitions of IST use, and categories of IST use by which efficacy outcomes were evaluated were. Descriptive statistics are used to present results. RESULTS: For skin, change in modified Rodnan skin score (mRSS) was numerically greatest with mycophenolate mofetil (MMF) treatment in patients with the earliest disease, reaching -10.8 points in the MMF group versus -4.8 points in the no IST group in patients with a disease duration ≤2 years. Other ISTs had improvements intermediate between that seen in the MMF and no IST groups. Forced vital capacity (mL) was stable over 52 weeks in patients in the MMF group compared to an around 160-mL decline over 52 weeks in no IST group. Differences in outcome were observed between antinuclear antibody subgroups, with greater difference in favor of MMF for skin and lungs being observed in anti-topoisomerase 1 autoantibody-positive patients. In contrast, anti-RNA polymerase III autoantibody-positive patients in both the no IST and MMF groups improved rapidly, with a decrease in mRSS. CONCLUSION: Taken together, our findings robustly support routine use of MMF in dcSSc and show benefit especially in early-stage disease. Those patients with high-risk antibodies for lung fibrosis might be especially suitable for MMF treatment.