SSc is an autoimmune connective tissue disease in which strong HLA associations have not been described. Anti-topo I antibodies are recognized, in general, in SSc patients with diffuse cutaneous involvement, whereas anti-ACAs are found in individuals with limited cutaneous involvement. We studied 95 Caucasian SSc patients, 44 with anti-topo I antibodies and 51 with neither anti-topo I nor ACA, for HLA-DR associations by using DNA typing techniques. We analyzed 181 normal Caucasian individuals in the same fashion. A significant association was observed in the anti-topo-I-positive patients with DRw11 (p = 1.7 x 10(-6), RR 4.2). The distribution of DRw11 alleles in these patients was significantly different from that observed in controls and could be accounted for by an increase in the frequency of the DRB1*1104 allele (p = 1.2 x 10(-9), RR 9.5). The DRw11 alleles were also associated with SSc with more tendon friction rubs (p = 0.006), which is a marker of more severe disease. In addition, a strong association was observed with anti-topo I antibodies and a particular sequence (aa 71-77) of the DQB1 chain (p = 0.02, RR 2.2). HLA associations in the case of SSc patients with anti-topo I antibodies are complex and involve at least two genes: HLA-DRw11, which appears to play a major role in determining the severity of the disease, and a DQ sequence, which associates with the development of the anti-topo I antibodies.