Purpose: Cervical cancer cells are addicted to the expression of the human papillomavirus (HPV)oncoproteins E6 and E7. The oncogencity of E6 is mediated in part by targeting p53a nd PDZfamilytumor suppressor proteins for rapid proteasomal degradation, whereas the E7 oncoproteinacts in part by coopting histone deacetylases (HDAC)1/2. Here, we examine the hypothesis thatinhibition of proteasome function andHDAC activity would synergistically and specifically triggercervical cancer cell death by the interruption of E6 and E7 signaling.Experimental Design: The sensitivity and molecular responses of keratinocytes and HPVpositiveand HPV-negative cervical cancer cells and xenografts to combinations of proteasomeand HDAC inhibitors were tested.The expression of HDAC1/HDAC2 in situ was examined in cervicalcancer, its precursors, and normal epithelium.Results: Cervical cancer cell lines exhibit greater sensitivity to proteasome inhibitors than doHPV-negative cervical cancers or primary human keratinocytes.Treatment of cervical cancer cellswith bortezomib elevated the level of p53b ut not hDlg, hScribble or hMAGI. Immunohistochemicalanalysis revealed elevated HDAC1/HDAC2 expression in cervical dysplasia and cervical carcinomaversus normal cervical epithelium. The combination of bortezomib and HDAC inhibitortrichostatin A or vorinostat shows synergistic killing of HPV-positive, but not HPV-negative, cervicalcancer cell lines. Similarly, treatment ofHeLa xenograftswith the combination of bortezomiband trichostatin A retarded tumor growth significantly more effectively than either agent alone.Conclusions: A combination of proteasome andHDACinhibitors, including bortezomib and vorinostat,respectively, warrants exploration for the treatment of cervical cancer.