To assess the efficacy of an endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitors (PDE5i) for treating systemic sclerosis (SSc)-related digital ulcers (DUs).This prospective, multicenter, observational cohort study recruited patients with active SSc-related DUs from 13 medical centers in South Korea. The primary outcome was time to cardinal ulcer (CU) healing. Secondary outcomes included time to new DU occurrence. Patients were followed up 4, 8, 12, and 24 weeks after treatment initiation.Sixty-three patients were analyzed. Their mean age was 49.9 ± 11.4 years and 49 were female. Twenty-eight had limited SSc. Forty-nine patients received the ERA, 11 patients received a PDE5i (nine sildenafil, one udenafil, and one tadalafil), and three patients received other medication. The hazard ratio (HR) for time to CU healing in the ERA group versus the PDE5i group was 0.75 (95% CI: 0.35-1.64, p = 0.47) in an unadjusted model and 0.80 (95% CI: 0.36-1.78, p = 0.59) in a model adjusted for age, sex, use of calcium channel blockers (CCBs), total DU numbers, and initial CU area. The HR for new DU development in the ERA group versus the PDE5i group was 0.39 (95% CI: 0.16-0.93, p = 0.03) in an unadjusted model and 0.32 (95% CI: 0.13-0.81, p = 0.02) in an adjusted model. No patients receiving CCBs developed new DUs at 24 weeks.Time to CU healing is comparable for ERA and PDE5i. An ERA is more effective in reducing new DU occurrence than PDE5i. CCBs may be effective as a background medication.