Using a murine transplantation model, we have investigated the function of the HPV16 E6 and E7 proteins in the development of radiation resistance in advanced cervical carcinoma. Constitutive high‐level expression of the HPV16 E6 oncogene in HPV negative human C33A cervical carcinoma cells was shown to induce rapid onset and radiation resistance in transplanted tumors when compared with tumors derived from E7 or vector transfected cells. The radiation‐ resistant, E6 tumor phenotype was not due solely to increased hypoxia, because all E6 tumors were shown to be uniformly hypoxic, and artificial induction of hypoxia, in E7 and control tumors, failed to produce the same degree of radiobiological resistance. Differential screening of a 1.2‐k human cancer cDNA array indicated that E6 tumors had up‐regulated expression of the DNA nucleotide excision repair gene excision repair cross‐complementation enzyme 1 (ERCC1). High‐level expression of ERCC1 mRNA and protein was found to be restricted to radiation‐resistant E6 tumors. In vitro maintenance of E6 and control vector‐expressing cells under anoxic conditions showed that ERCC1 expression was induced preferentially in E6‐ expressing cells. These data indicate that the HPV16 E6 protein may influence the response to therapy of cervical carcinoma by inappropriate activation of DNA repair mechanisms.