Objective: Interferon (IFN)-1 signatures are a hallmark of patients with systemic sclerosis (SSc). However, its significance in clinical stratification and contribution to deterioration still need to be better understood. Methods: For hypothesis generation, we performed single-cell RNA sequencing (scRNA-seq) on skin biopsies (four patients with SSc and two controls) using the BD Rhapsody platform. Two publicly available data sets of skin scRNA-seq were used for validation (GSE138669: 12 patients with diffuse cutaneous SSc [dcSSc] and 10 controls; GSE195452: 52 patients with dcSSc and 41 patients with limited cutaneous SSc [lcSSc] and 54 controls). The IFN-1 signature was mapped, functionally investigated in a bleomycin plus IFNα-2 adenovirus-associated virus (AAV)-induced model and verified in an SSc cohort (n = 61). Results: The discovery and validation data sets showed similar findings. Endothelial cells (ECs) had the most prominent IFN-1 signature among dermal nonimmune cells. The EC IFN-1 signature was increased both in patients with SSc versus controls and in patients with dcSSc versus those with lcSSc. Among EC subclusters, the IFN-1 signature was statistically higher in the capillary ECs of patients with dcSSc, which was higher than those in patients with lcSSc, which in turn was higher than those in healthy controls (HCs). Endothelial-to-mesenchymal transition (EndoMT) scores increased in parallel. Deteriorated bleomycin-induced dermal fibrosis, EndoMT, and perivascular fibrosis and caused blood vessel loss with EC apoptosis. Vascular myxovirus resistance (MX) 1, an IFN-1 response protein, was significantly increased both in total SSc versus HC skin and in dcSSc versus lcSSc skin. Baseline vascular MX1 performed similarly to skin score in predicting disease progression over 6 to 34 months in total SSc and was superior in the dcSSc subpopulation. Conclusion: The EC IFN-1 signature distinguished SSc skin subtypes and disease progression and may contribute to vasculopathy and fibrosis.