This report describes the association of HLA-DR phenotypes in a population of 91 Caucasian melanoma patients compared with 106 Caucasian controls from the Sunbelt region of the United States. Over 75% of both patients and controls were born in Alabama or a surrounding state. There was a significant increase in the frequency of HLA-DR4 (x2 = 12.8; p = 0.0003). This was present in 38.5% of the patients compared to a 16.0% frequency in the controls, producing a relative risk of 3.3. The difference in DR4 distribution remained significant after correcting for the number of antigens (pc = 0.0018). The patients were then grouped into two categories, “low risk” and “high risk,” based on their clinically assessed risk at presentation for metastatic involvement. The decrease of DR3 in the high-risk group (x2 = 5.2; p = 0.02) suggested that it may represent a marker for long-term survival. Thus, it appears that susceptibility to developing melanoma may be associated with DR4 while survival may be associated with DR3. © 1982, American Association for Cancer Research. All rights reserved.