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Vesicular Stomatitis Virus (VSV) is currently being studied as a candidate oncolytic agent due to its ability to induce apoptosis in a variety of cancer cells. Previous studies have shown that Matrix (M) protein mutants of VSV, such as rM51R-M virus, act as selective anti-cancer agents by targeting cancer cells while sparing normal cells. Our goal was to promote the use of VSV for the treatment of cervical cancers. The cervical cancer cell line SiHa has been shown in previous studies to be permissive to infection and killing by VSV. We hypothesized that cervical cancer lines are sensitized to VSV due to blockage of the type-1 interferon (IFN) response by Human Papillomavirus (HPV) oncoproteins. However, our results indicated that SiHa cells retained their ability to respond to type I IFN and were sensitive to killing by both wild-type (wt) and M protein mutant VSV (rM51R-M virus) when infected at a high multiplicity of infection. Another cervical cancer cell line, C4-II, was more resistant than SiHa cells to infection by VSV. To augment killing of cervical cancer cells by VSV, we infected cells in the presence of natural compounds with known anti-cancer activities. Curcumin synergized with VSV to kill both SiHa and C4-II cells, while resveratrol, flavokavain B, Echinacea, and quercetin did not offer an added benefit. In conclusion, our results show that cervical cancer cells exhibit resistance to VSV infection but may be sensitized to VSV-induced oncolysis by the addition of curcumin.