Associations were sought between specific histocompatibility antigens (HLA) of the human major histocompatibility complex and the incidence of head and neck squamous cell carcinoma (SqCC). Seventy sequential patients with SqCC and 217 control subjects from the same geographic region were typed for HLA-A, HLA-B, and HLA-DR loci. These results were compared. Multivariate statistical analysis using stepwise logistic regression revealed significant associations between the incidence of SqCC and HLA-B14, HLA-DR3, and HLA-DR4 as well as smoking and the sex-smoking interaction. The authors concluded that certain host factors, including genetic constitution, and behavioral characteristics (i.e., smoking) as well as tumor biology, can influence the development of SqCC. The mechanism(s) of these associations may involve as yet undefined relationships between HLA region genes and the immune response.