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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 …