Naturally occurring strains of Newcastle disease virus (NDV) are currently being investigated in multiple clinical trials for oncolytic cancer therapy in the United States and abroad. We have previously reported, for the first time, the development of recombinant NDVs designed for enhanced cancer therapeutic efficacy. Specifically, we have shown that NDV engineered to express interleukin-2 (IL-2) generates a robust therapeutic response associated with increased tumor-specific T-cell infiltration after intratumoral administration in mice. We have now demonstrated that this therapeutic response is dependent on T cells and we have investigated the potential to focus the NDV-induced immune response toward a tumor-associated antigen (TAA) to enhance the inherent therapeutic efficacy of NDV further. We found that intratumoral treatments of tumor-bearing mice with recombinant NDV expressing a model TAA elicited an enhanced tumor-specific response, resulting in a significant increase in the number of complete tumor regressions compared with control NDV. Additionally, coadministration of NDV expressing a model TAA with NDV expressing IL-2 enhanced the TAA-directed response and led to more complete tumor regressions. Our results show that TAA-directed immunotherapy by oncolytic recombinant NDV alone or in combination with IL-2 results in an enhanced therapeutic efficacy and warrant consideration in the development of cancer therapies based on the use of oncolytic NDV.