We established a new syngeneic murine model of oral squamous-cell carcinoma (SCC) to analyze the potential role of immune recognition determinants in the early development of oral cancer. In this study, we examined whether SCC that undergo transformation and development in the absence of specific immunity exhibit differences in tumorigenicity that relate to differences in expression of CD80, CD86 or MHC class I. Mucosal keratinocytes from BALB/c mice were transformed in vitro with 4-nitroquinolone-1-oxide (4-NQO) and inoculated into SCID mice to obtain tumorigenic cell lines. Five SCC cell lines were re-isolated from tumors, and 4 retained cytokeratin and beta4-integrin markers of epithelial origin. Their growth was compared in BALB/c and in congenic SCID mice to establish whether the cell lines exhibit differences in immunogenicity. Three lines that showed slower growth or completely regressed when implanted in immune competent hosts retained or developed increased expression of CD80 during development in SCID mice. Conversely, 2 SCC lines that lost expression of CD80 after passage in vivo grew progressively in immune-competent hosts. MHC-class-I and CD86 expression did not correlate with tumorigenicity. These observations provide evidence that decreased expression of CD80 may serve as a marker for increased tumorigenicity during early development of oral SCC. The development of this new murine oral SCC model should prove useful in determining the potential effects of CD80 expression on the immune pathogenesis and therapy of SCC.