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Problem: Patients with head and neck squamous cell carcinoma (HNSCC) have significant dysfunction of anti-tumor immunity. In addition, these patients experience a high degree of psychological distress associated with the diagnosis, physical effects, and the ablative treatments designed to cure cancer in the upper aerodigestive tract. Few studies, however, have longitudinally and systematically assessed the extent to which psychosocial factors may impact on immune responses in this population. Methods: Patients with HNSCC undergoing treatment with surgery, radiotherapy, or both were administered a battery of validated questionnaires to assess mental status and cognition, life stress, social support, coping, psychological distress, health behaviors, and quality of life at 2 time points: pretreatment and 6 weeks posttreatment. Peripheral blood was obtained at these 2 time points and CD4+, CD8+, and gamma-delta T cell subsets were isolated and analyzed by flow cytometry. Pearson-zero order correlations were performed between psychosocial stressors and percentages of T cell subsets. Results: Preliminary analysis of 38 patients showed that behavioral disengagement (giving up attempts to deal with the cancer diagnosis) prior to treatment was correlated to decreased levels of CD8+ T cells both pretreatment and posttreatment, while an increase in coping-planning (devising strategies to deal with the problem) after the diagnosis of carcinoma was correlated with increased levels of CD4+ T cells. Conclusion: Patients who respond to the diagnosis of cancer with denial/avoidance may be at risk for T cell immune dysfunction. Health care professionals may be instrumental in recognizing and helping patients with adjustment difficulties and negative coping behaviors after diagnosis of and during treatment for HNSCC. Significance: Understanding the effect of psychosocial factors on anti-tumor immunity is important in order to develop effective cognitive behavioral stress management interventions that aim to enhance or sustain immune function and overall health status through stress management techniques including effective coping and use of efficacious social networks. Support: None reported.