The effect of retroviral-mediated interferon-gamma (IFN-gamma) gene transfer on major histocompatibility complex (MHC) class I and II antigen expression was investigated in 13 head and neck squamous carcinoma cell lines. Six cell lines exhibited increased MHC class I expression, and 10 exhibited increased MHC class II expression after IFN-gamma gene transfer. Differences in MHC antigen expression between parental and transduced cell lines were significant (P = 0. 002) only for cell lines that upregulated MHC class II expression. After incubation in medium containing 100 U/mL recombinant IFN-gamma, or in medium from IFN-gamma retrovirus-transduced NIH 3T3 cells, 12 cell lines significantly upregulated MHC class I expression, and 9 significantly upregulated MHC class II expression. Only cell lines that exhibited increased MHC class II expression after retroviral transduction also upregulated class II expression with exogenous IFN-gamma treatment. Thus some head and neck squamous carcinoma cell lines can upregulate MHC class I and II expression after exogenous application of either IFN-gamma or IFN-gamma retroviral transduction. These are promising findings for head and neck cancer immunotherapy and gene therapy.