Survival for patients with advanced cancer has remained dismal, and there is a need for new treatments. In this context viral immune therapy is a promising novel strategy. Intravenous delivery confers advantages as it enables simultaneous treatment of primary tumour and any metastatic deposits but host defences limit Vaccinia virus's (VV) ability to infect tumour after systemic administration. Although Vaccinia virus can potentially be delivered systemically as it can evade both complement and neutralising antibodies, our investigations have revealed that VV cannot effectively infect tumour cells in immunocompetent mice after systemic delivery. Strikingly, we observed that if macrophages were depleted in the mice using clodronate liposomes, VV infection of tumours was dramatically enhanced. However, clodronate liposomes non-selectively deplete macrophages and potentially diminish any beneficial macrocytic activity in the tumour microenvironment unrelated to viral clearance. Consequently, a more clinically appropriate agent is needed. Macrophages recognise and ingest pathogenic microorganisms through phagocytosis, a process for which several lines of evidence have highlighted an important role for phosphatidylinositol 3-kinases. Accordingly, in these investigations I have evaluated the effect of selective PI3K inhibitors on macrophage phagocytosis in vitro and demonstrated that IC87114 (a PI3 kinase delta inhibitor) is effective at reducing uptake of VV by macrophages, confirming this finding in transgenic macrophages with a mutant of the PI3 kinase delta isoform knocked in. Subsequently, it was confirmed that IC87114 affects attachment of the virus to macrophages but plays no role in internalisation of the virus. In cancer cells cultured in isolation, the inhibitor has no direct cytotoxic effect and when combined with VV, in the same in vitro system, there is no change in the amount of cell death compared to VV alone treated controls. Biodistribution studies have established that IC87114 combined with VV results in statistically significantly higher levels of virus detected in tumours compared to the groups treated with VV alone, with similarly limited off-target effects. Finally, three different efficacy studies have demonstrated statistically significantly superior tumour responses in the VV+IC87114 group. In conclusion, PI3k delta blockade is an effective strategy for enhancing systemic delivery of VV in a preclinical model and could be a useful adjuvant in VV clinical trials.