Plasma exchange (PEX) is a technique that has been applied to the treatment of many immunological disorders, including connective tissue diseases. The crucial role of some humoral factors in the pathogenesis of systemic sclerosis (SSc) could explain the good clinical results obtained in terms of slowing down the disease progression, but the efficacy of PEX in the treatment of SSc is not yet well defined, owing to the lack of controlled studies and validated parameters of disease activity. To demonstrate the long-term efficacy of PEX in the treatment of SSc we treated a group of 28 SSc patients affected with recent onset and/or rapidly progressive disease. Most of these had a diffuse form of SSc, with anti-Sc170 antibody as a disease marker. Before and after long-term PEX treatment we evaluated disease activity parameters including the serum levels of interleukin 2 soluble receptor (sIL-2R) and aminoterminal type III procollagen peptide (PIIINP), plus the percentage of DR+ T cells in the peripheral blood. We also assessed clinical parameters of total skin score and total visceral score. The same parameters were evaluated in 25 SSc patients who did not satisfy the admission criteria for PEX, treated long-term with drugs only. At baseline, serum PIIINP and sIL-2R levels and the percentage of DR+ T cells were significantly increased in PEX patients as compared to others. Following long-term PEX treatment, all the laboratory parameters significantly decreased and the clinical scores showed a slight but not significant improvement. Conversely, in the other group of SSc patients treated for the same period with drugs only, no significant change of laboratory parameters was detected and the clinical scores slightly worsened. Our data suggest that long-term PEX therapy seems to be effective in slowing down the clinical course of patients with severe and rapidly progressive SSc.