The HLA-A, B, C, and DR loci of 136 patients with progressive systemic scleroderma have been determined. The patients were classified according to the extent of their skin affection and into groups with or without immunologic and inflammatory signs of the disease. The antigens of the A locus did not show any significant deviations in frequency of occurrence. An increase of HLA-B8 and HLA-DR3 was only proved in the male patient group. Furthermore, in the HLA-DR gene locus, an increase in frequency of HLA-DR1, 2, 3, and 5 could be found. However, in the total set of patients, only the correlation of HLA-DR5 with progressive systemic scleroderma reached significance. Patients suffering from the CREST (calcinosis, Raynaud's phenomenon, esophagus, sclerodactyly, and telangiectasia) syndrome showed an increase of HLA-DR1. Patients with inflammatory signs of the scleroderma showed an accumulation of HLA-DR2. Several HLA-linked genes control the susceptibility to scleroderma.