Sera from 224 patients with systemic sclerosis (scleroderma) were analyzed for circulating antibodies against an antigenic determinant characterized by two molecules of galactose in alpha 1-3 linkage. About 45% of the patients were found to have values above the normal range. The mean antibody level was significantly higher than that found in normal subjects (p less than 0.001) or in patients with primary Raynaud's phenomenon who were included as controls. The mean level of anti-Gal antibodies correlated with the degree of skin and internal organ involvement, as well as with the presence of progression or inflammation. Furthermore, when patients with early onset disease were analyzed, high levels of anti-Gal antibodies were present in the subgroups characterized by evidence of progression or inflammation, whereas patients with stable disease did not differ from the controls. We conclude that humoral immunity against Gal alpha 1-3 Gal is an early feature of scleroderma, may be important for its pathogenesis, and may provide a more sensitive tool to detect disease activity.