Oncolytic viruses that selectively infect tumor tissues are a novel technique for stimulating antitumor immunity, and they show great promise for synergy with cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) blockade. If an accessible lesion is identified, an intratumoral injection of an oncolytic virus is given. Viruses damage infected cancer cells in different ways, including direct virus-mediated cytotoxicity and induction of tumor-specific immunity. For example, Newcastle disease virus (NDV) is a nonpathogenic avian paramyxovirus with robust type I interferon-inducing and oncolytic properties and strong clinical safety data. Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy based on the JS1 strain of herpes simplex virus (HSV) type 1 engineered to express human granulocyte macrophage colony-stimulating factor (GM-CSF). T-VEC not only directly lyses cells but also employs local GM-CSF accumulation to attract and induce dendritic cells after they engulf dying tumor cells. Priming of antigen-specific T-cell immunity subsequently occurs, in which CTLA-4 is known to suppress the early stages of T-cell activation. Indeed, a compelling preclinical study found that combination therapy with NDV and CTLA-4 blockade led to rejection of pre-established distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models. Furthermore, in a phase Ib study, the combination of T-VEC and ipilimumab in patients with advanced melanoma led to durable responses in 10 of 18 patients (56%), with complete responses in 33% of patients and no unexpected toxicity. The phase II part of the study is currently enrolling patients (NCT01740297).