Dermatomyositis is a rare yet devastating autoimmune disease characterized by inflammatory and vasculopathic changes in skin and muscle. Dermatomyositis and systemic lupus erythematosus (lupus) skin lesions have overlapping clinical and histopathological features but show disparate responses to available therapeutics, with dermatomyositis skin disease often relapsing and being recalcitrant. To investigate dermatomyositis immunopathogenesis, nonlesional skin, lesional skin, and circulating immune cells from patients with dermatomyositis were analyzed using single-cell RNA sequencing. Samples were analyzed in parallel with lesional and nonlesional lupus skin, healthy control skin, and peripheral blood from all three patient groups. We demonstrate a pervasive type I interferon signature in dermatomyositis stroma that persisted in culture and was distinguished from lupus by up-regulation of vascular endothelial growth factor and interleukin-18 signaling in dermatomyositis keratinocytes. Furthermore, endothelial cells in lesional dermatomyositis exhibited decreased proliferation, which was not observed in lupus skin. Using cell communication networks, we identified a population of dermatomyositis-specific monocytes interacting with nonproliferating endothelial cells. Coculture of monocytes from patients with dermatomyositis with endothelial cells resulted in increased endothelial cell apoptosis, which was inhibited by Janus kinase 1 (JAK1) blockade. JAK1 inhibition also resulted in reversal of dermatomyositis stromal and inflammatory signatures. Together, our data provide a comprehensive cross-disease characterization of lesional and nonlesional skin in dermatomyositis and implicate monocyte-mediated endothelial cell dysfunction in dermatomyositis vasculopathy. Moreover, these results suggest that JAK inhibition may offer a suitable therapeutic intervention for refractory skin disease.