The aim of this study was to evaluate the clinical and immunomodulatory effects of extracorporeal photochemotherapy (ECP) in systemic sclerosis (SSc). We enrolled 16 patients with diffuse cutaneous SSc, who received 12 ECP treatments in total. After ECP treatments, the dermal thickness reduced and the mobility of joints improved. Internal organ involvement did not deteriorate. The percentages and numbers of peripheral Th17 cells decreased, the values of Tr1 and Treg cells increased, and the suppressor capacity of Treg cells improved. Interestingly, we found a positive correlation between the reduction of IL-17 levels and skin thickness measured by ultrasound. Moreover, levels of CCL2 and TGF-beta decreased, while the concentration of IL-1Ra, IL-10 and HGF elevated during the therapy. ECP treatments contribute to the restoration of disproportional autoimmune responses and attenuate fibrotic processes, thus decelerate the disease progression. Accordingly, ECP can be a useful element of novel treatment modalities proposed for SSc.