Abstract We recently reported that acute concomitant infection in a tissue distant from the tumor results in the trafficking of tumor-specific CD8+ T cells from the tumor microenvironment to the infection site and to accelerated tumor growth and host death. However, we hypothesized that anti-viral responses within the tumor (rather than distant from it), possibly even without productive viral replication, can reprogram the local tumor microenvironment and lead to long-term tumor regression. Indeed, we discovered in a mouse model of melanoma (B16-F10), that injection of live influenza (A/H1N1/PR8), heat-inactivated influenza, or live vesicular stomatis virus (VSV) results in no observable mordibity or mortality, but significantly inhibits tumor growth (with 60% of the mice surviving more than 50 days). We observed similar results in a 4T1 breast cancer model where, likewise, such virus-associated treatments significantly decreased the tumor area compared to vehicle-treated controls. Interestingly, prior influenza exposure completely abrogated the anti-tumor response after local re-exposure, suggesting that primary anti-viral responses, but not secondary immune responses, at the tumor site may be a novel type of immunotherapy. This finding may explain why infections in cancer patients have been reported to both decrease and increase cancer-specific mortality. Future studies will seek to determine if combination immunotherapies utilizing anti-viral immune responses may augment tumor regression and whether specific viruses are favored based on the cancer type. The overall goal of our work is to translate these findings into clinical trials and cancer patient treatment regimens that improve and save cancer patient lives.