A low molecular weight cutaneous antigen was found to stimulate the release of macrophage migration inhibition factor from circulating lymphocytes of patients with diffuse scleroderma. The antigen had a molecular weight of approximately 3,500 and contained RNA and polypeptides, but no hydroxyproline. Lymphocytes from patients with the CREST syndrome, rheumatoid arthritis, and from normal controls did not respond to the antigen. An immune response to this antigen may be a factor in the pathogenesis of diffuse scleroderma.