Abstract High-risk human papillomaviruses(HPVs) are associated with a subset of head and neck squamous cell carcinomas (HNSCC) as well as most of cervical cancers. HPV type 16 (HPV-16), which is found in the vast majority of HPV-positive HNSCC, encodes for three oncogenes: E5, E6, and E7. Previously, we learned that HPV-16 E7 is the dominant oncoprotein in head and neck cancer in mice. More recently, we learned that tissue specific inactivation of the retinoblastoma-susceptibility gene, pRb, a well known cellular target of HPV E7 and a member of the “pocket protein’ family, was not sufficient to account fully for the oncogenic properties of E7 in HNSCC. E7 is known to inactivate not just pRb, but also other related cellular proteins, specifically p107 and p130. This led to our current study in which we have observed that the combined loss of pRb and p130, or pRb and p107 leads to increased susceptibility to head and neck cancers in comparison to mice conditionally disrupted only for pRb, yet are not sufficient to account fully for E7's oncogenic potential in HPV-associated head and neck carcinogenesis. Additionally, combinatorial loss of pRb and p130, or pRb and p107 partially mediates E7-induced acute phenotypes in head and neck epithelia. Taken together, our results indicate that the combined inactivation of two pocket proteins are not sufficient to fully recapitulate E7 oncogenic properties in HNSCC. We conclude that inactivation of all three pocket proteins is necessary to account for E7's carcinogenic properties in HNSCC or that other targets of E7 contribute to its carcinogenic potential in HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2100. doi:10.1158/1538-7445.AM2011-2100