Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most frequent cancer worldwide. SCC is the most common malignant tumor of the oral cavity with over 35,000 cases and 8,000 deaths reported in the United States each year. Previous case studies have reported increased incidence of HNSCC in patients on immunosuppressive therapy for organ transplantation. The results of these studies indicate that effective immune surveillance is important for preventing emergence of HNSCC. HNSCC may also inhibit immune response to tumor cells, which may be responsible for progression. We previously reported induction of metastatic HNSCC in p53 null mutant mice. Despite induction with the potent carcinogen dimethylbenzanthracene, each mouse developed only 1-2 primary tumors with a relatively long induction period of 22 weeks. We hypothesized that immune surveillance might eliminate early tumor cells resulting in the relatively small number of primary tumors and long induction time. To test this hypothesis we performed the induction protocol in nude mice which have defective T lymphocyte function. Decreased T lymphocyte function resulted in reduced tumor latency and increased tumor formation. Immunohistochemical studies showed that expression of cell cycle regulatory proteins is similar in mouse and human HNSCC. However, distinct differences exist between primary and metastatic tumors from nude and wild-type mice. We also determined that lymphocytes react to metastatic tumor cells by upregulating immunoglobin gene expression but are prone to apoptosis via decreased expression of survival factors and upregulation of cell death genes.