To investigate the function of S100A8, a member of the calcium-binding S100 protein family, in oral tumorigenesis. We analyzed its cellular distribution and its serum level in patients with squamous cell carcinoma and normal controls. We investigated the histopathologic features by tissue microarrays (TMAs) including 8 normal, 66 hyperplastic and dysplastic and 26 oral squamous cell carcinoma (OSCC) tissue cores. The serum level of S100A8 was measured by an enzyme-linked immunosorbent assay using 33 healthy volunteers, 20 patients with hyperproliferative lesions and 23 patients with OSCC. The TMA analysis resulted in different findings. The strongest expression of S100A8 was found in severe dysplasias and carcinoma in situ. In tumor tissue an increased expression occurred only focally. In the normal tissue cores the epithelium showed a moderate reaction, but basal and parabasal cells were completely negative. The serum levels of S100A8 were marginally reduced in cancer patients. The expression between healthy controls and patients with hyperproliferative lesions displayed no difference. The expression of S100A8 is helpful only in the transition from severe dysplastic tissue to cancer.