Susceptibility to a variety of malignancies has been linked to human leukocyte antigen (HLA) genes, including the HLA class II allele DQB1*0301. To determine whether melanoma risk is associated with HLA class II alleles, molecular oligotyping of HLA class II-DRB1, -DQA1 and -DQB1 genes was performed for 45 patients with melanoma. The DQB1*0301 allele was present in 56% of melanoma patients vs. 27% of 200 local Caucasian controls. This difference was highly significant (Bonferroni's-corrected chi-square p = 0.003, OR = 3.4). No other class II allele tested was present at significantly increased or decreased frequency in melanoma patients. Furthermore, presence of DQB1*0301 in melanoma patients was associated with advanced disease. Melanoma patients carrying the DQB1*0301 allele presented on average with thicker primary tumors (mean 3.7 mm vs. 1.8 mm, 2-tailed p = 0.02) and were more likely to present with regional or distant metastatic disease (stages III-IV, 44% vs. 5%, chi-square p = 0.003), compared to melanoma patients without DQB1*0301. Risk of melanoma incidence or progression may be influenced by DQB1*0301 or a closely linked gene.