Systemic sclerosis (SSc) is a connective tissue disease characterized by excessive fibrosis, microvasculopathy, and autoimmunity. Endothelial cell (EC) injury and subsequent endothelial cell dysfunction is believed to be an initial event that eventually leads to a vicious pathogenic cycle. This process is further enhanced by defective angiogenesis and vasculogenesis, as the vascular repair machinery does not work properly. Endothelial progenitor cells (EPCs) are functionally and quantitatively insufficient to recover the endothelium in SSc patients. The dysfunctional ECs and EPCs not only trigger the formation of typical vascular lesions, such as progressive intimal fibrosis in small arteries and the loss of capillaries, but also promote a series of inflammatory and profibrotic processes, such as endothelial-mesenchymal transition and recruitment and accumulation of monocytic EPCs with profibrotic properties. These processes together contribute to the accumulation of extracellular matrix in the affected tissue. This review features current insights into the roles of ECs and EPCs in the pathogenesis of SSc. Cite this article as: Kuwana M, Ota Y. Endothelial cells and endothelial progenitor cells in the pathogenesis of systemic sclerosis. Eur J Rheumatol 2020; 7(Suppl 3): S139-46.