A high incidence of locoregional failure contributes to the poor overall survival rate of around 50% for patients with squamous cell carcinoma of the head and neck (SCCHN). In vitro and in vivo preclinical work with adenovirus-mediated wild-type p53 gene transfer using the recombinant p53 adenovirus (Ad-p53) has shown its promise as a novel intervention strategy for SCCHN. These data have translated into Phase I and Phase II studies of Ad-p53 gene transfer in patients with advanced, locoregionally recurrent SCCHN. The safety and overall patient tolerance of Ad-p53 has been demonstrated. Of 15 resectable but historically noncurable patients in the surgical arm of a Phase I study, 4 patients (27%) remain free of disease, with a median follow-up time of 18.25 months. Surgical and gene transfer-related morbidities were minimal. These results provide preliminary support for the use of Ad-p53 gene transfer as a surgical adjuvant in patients with advanced SCCHN. The implications of our findings for the management of SCCHN in general are discussed.