Background: Extracorporeal photochemotherapy (EXP) is an immunomodulating therapy that has been used in a limited number of patients with systemic sclerosis (SSC) with controversial results. The present study was performed to evaluate the efficacy and safety of extended EXP with extracorporeal application of liquid 8-methoxypsoralen (8-MOP) in the treatment of SSC. Methods: Eleven women with progressive SSC of recent onset were treated for a period of 16–57 months. Skin changes, physical performance, extracutaneous manifestations, and quality of life were evaluated before initiation of EXP and at regular intervals thereafter. Results: From the start to the last set of EXP, we observed an overall improvement and/or stabilization of skin changes and physical performance in 5 of 11 patients (45%). Extracutaneous manifestations deteriorated in 10 of 11 patients (91%) (P<0.05), and quality of life deteriorated in 9 of 11 patients (82%) from a mean score of 10 before, to 17 at the last set of EXP (P<0.05). No major side effects were noted. Conclusion: Extended EXP with extracorporeal administration of 8-MOP is a safe and well tolerated treatment modality. However, it provides only (minor) improvement of skin changes of a subset of SSC patients and does not beneficially influence extracutaneous manifestations and quality of life.