Survival from advanced primary or recurrent Squamous Cell Carcinoma (SCC) of the head and neck (H&N) is poor. More accurate detection of primary tumors and recurrence may provide ways to improve survival. No standard serum tumor marker is routinely used for surveillance of SCC-H&N. In this paper, we evaluated the performance characteristics of the MPS-H tumor marker test for the quantitative measurement of "MPS-H" heat-generated immunoreactive proteins and assessed the clinical utility of this marker in the detection and monitoring of SCC-H&N. In approximately 92% of the subjects having no evidence of SCC-H&N, the MPS-H levels were lower than 15 ng/mL. In 76% of patients having SCC-H&N at various stages (T1-T4), the MPS-H level was > 15 ng/mL (range: 20-200 ng/mL). In addition, we found a statistically significant correlation between PET positive cases and high MPS-H serum levels in SCC-H&N patients with recurrent disease. These results suggest that MPS-H may provide an initial screening test that would allow for selective PET imaging in these patients. Furthermore, we found that there was greater expression of MPS-1 in tumors of higher histological grades. Thus, in tumors with more histological aggressiveness there is more MPS-1, indicating the potential usefulness of this marker in prognosis for SSC-H&N. Considering the immunohistochemical, serological, and FDG-PET data presented here, and the compelling need to expedite the early diagnosis of primary and recurrent epithelial malignancies of the head and neck, we are further evaluating the system of MPS antigens in a large patient population as a tool for the early serologic and histologic diagnosis of SCC-H&N.