Normal adult human dermal fibroblasts were cultured in the presence of sera from 142 subjects. Results of a fibroblast proliferation assay revealed that 16 of 42 patients with scleroderma, 1 of 25 with rheumatoid arthritis, 3 of 10 with systemic lupus erythematosus, 2 of 3 with mixed connective tissue disease and 0 of 42 normal controls had values outside the normal range. The activity of fibroblast growth promoting factor (FGPF) in the scleroderma group correlated with the skin involvement but not with involvement of any other organ system. The levels of FGPF were higher in the first 2 years of disease duration than at any other time. Our data suggest that fibroblast activation may be a key process in the pathogenesis of scleroderma.