Head and neck squamous cell carcinomas (HNSCC) manifest various clinical behaviors according to their origin, i.e., from various parts of the head and neck mucosa. However, genetic factors involved in the carcinogenesis of HNSCC in different tissues have not yet been studied and evaluated. Three hundred and two specimens of HNSCC were characterized for allelic loss of certain areas of the genome, i.e., 3p21, 9p21 and 17p13, and were examined for genetic factors that might correlate with the tissue specificity of HNSCC and influence their clinical features. Loss of heterozygosity (LOH) at 3p21, 9p21 and 17p13 was detected in 54.5%, 57.4% and 57.1% of the informative cases, respectively. The frequencies of LOH in hypopharyngeal and in laryngeal cancers were significantly higher than in oral cancers. There were significant correlations between LOH at 3p21 and lymph node involvement and between LOH at 17p13 and tumor size, resulting in positive correlations with clinical stage of HNSCC in the patients. These results indicate that not only the functions of tumor suppressor genes differ among HNSCC in various regions, but also that allelic loss plays a key role in the acquisition of a malignant phenotype of these tumors.