Recent developments in the field of oncolytic or tumor-selective viruses have meant that the clinical applications of these agents are now being considered in more detail. Like most cancer therapies it is likely that they will be used primarily in combination with other therapeutics. Although several reports have shown that oncolytic viruses can synergize with chemotherapies within an infected cancer cell, it would be particularly important to determine whether factors released from infected cells could enhance the action of chemotherapies at a distance. Here, we demonstrate in vitro synergy between oncolytic vaccinia and taxanes. However, we also show, for the first time, that this synergy is at least partly due to the release of factors from the infected cells that are capable of sensitizing surrounding cells to chemotherapy. Several cellular factors were identified as being mediators of this bystander effect, including type I interferon released soon after infection and high-mobility group protein B1 (HMGB1) released after cell death. This represents the first description of these mechanisms for beneficial interactions between viral and traditional tumor therapies. These data may provide a direct basis for the design of clinical trials with agents currently in the clinic, as well as providing insight into the development of next generation viral vectors.