This is the second case report of familial scleroderma (systemic sclerosis) in South Carolina. The family includes two cases of scleroderma meeting American Rheumatism Association criteria, one of systemic sclerosis sine scleroderma, and two other cases of undifferentiated connective tissue disease with features of scleroderma spectrum disorders; there are also two cases of Raynaud's phenomenon (one associated with rheumatoid arthritis), for a total of seven affected relatives. Evidence of scleroderma spectrum disorders was sought in six siblings of the two co-index cases and in 23 of the 35 offspring. Laboratory studies included antinuclear antibody determinations and typing for the following genetic markers: HLA (A, B, C, DR), complotypes, Gm and Km allotypes, and alpha-1 antitrypsin phenotypes. No common genetic markers restricted to affected members of this family were found, and no environmental exposures were detected that could explain this familial clustering of cases. This report should, however, add to the slowly accumulating information on the genetic characteristics of families at unusually high risk for scleroderma spectrum disorders. Positive antinuclear antibody tests at a titer of 1/40 or higher were present in 57 percent of the first-degree relatives of the affected cases.