Learning to identify tumor and tumor-associated antigens in patients with squamous cell carcinoma of the head and neck (HNSCC) may bring about better diagnostic and prognostic evaluations of the disease, innovative therapies based on immunological approaches, and a better understanding of the biology of tumorigenesis. Serological analysis of tumor antigens by recombinant cDNA expression cloning (SEREX) has been used to identify antigens in head and neck cancer to which patients have produced high-titered IgG antibodies. Four cDNA expression libraries have been screened with sera from 6 head and neck cancer patients. Thirty-seven individual gene products were identified. Thirty-one previously characterized proteins and 6 genes coding for molecules that are only partially characterized or novel were isolated. Tissue expression was evaluated by Northern blot analysis, RT-PCR, and in one case, quantitative real-time PCR (qPCR) using Taqman technology. Clone AU-HN-15 encoded a protein highly expressed in HNSCC tissues and cell lines. Tissue adjacent to the tumor had negligible expression. There was low or negligible expression in normal tissues, except for the brain and thymus. AU-HN-15 is identical to KIAA0530; it is an uncharacterized protein previously cloned from brain tissue and has a zinc finger domain. The cDNA encoding this protein has also been isolated in SEREX screens of testicular cancer, breast cancer, and colorectal cancer. Whether AU-HN-15 represents a tumor-antigen target suitable for prognostic or therapeutic purposes is still being analyzed.