In an uncontrolled clinical trial, plasmapheresis combined with prednisone and cyclophosphamide therapy produced clinical improvement in 14 of 15 scleroderma patients with varying degrees of skin and internal organ involvement. All improved patients showed a gradual loosening of hide-bound skin, relaxation of contractures, and healing cutaneous ulcers, when present. Severe gastrointestinal symptoms were ameliorated in 4 patients, severe polymyositis was largely reversed in 2 patients, and pulmonary and cardiac function was improved in others. After initial improvement, however, 2 patients died during the period of study and another withdrew unimproved. Antinuclear antibody (ANA) titers declined relatively more than total IgG levels with plasmapheresis in 6 of the 9 patients who had elevated titers. Increased levels of endothelial cell cytotoxic activity found in 11 of the 15 patients were significantly reduced by plasmapheresis. Elevated levels of circulating immune complexes were found in only 4 of the 15 patients. Skin biopsies from adjacent sites taken before and after plasmapheresis in 10 patients all showed less swollen dermal collagen with increased ground substance between collagen bundles in the second biopsy. Although the effects of plasmapheresis cannot be dissociated from those of the immunosuppressive drug therapy, our results suggest that plasmapheresis combined with immunosuppressive drug therapy may find a place in the management of patients with moderate to severe scleroderma. This study implicates circulating factors in the pathogenesis of the disease.