In this study, we explored the functional relevance of caspase-8 and the p53 status in etoposide-induced apoptosis by using two HNSCC cell lines: an etoposide-resistant HOC313 cell line that is deficient in caspase-8 which carries the temperature-sensitive mutant p53G285K; and etoposide-sensitive Ca9-22 cell line that expresses wild-type caspase-8 and the p53R248W mutant, which has no recognizable temperature-sensitive properties. Here, TP53 is linked to head and neck squamous cell carcinoma.