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Objective Recombinant Newcastle disease virus (rNDV) as oncolytic agent has been shown to be effective for cancer therapy.Methods: In this study, we generated recombinant lentogenic NDVs expressing IL-2 (rNDV-IL-2), TRAIL (rNDV-TRAIL) or both IL-2 and TRAIL (rNDV-IL-2-TRAIL) at genomic location between HN and L, the parental virus expressing EGFP (rNDV-EGFP) as control.Results: In vitro experiments indicated that these recombinant viruses expressed corresponding gene products, which had been demonstrated biologically active.We demonstrated that rNDV-TRAIL and rNDV-IL-2-TRAIL significantly enhanced the intrinsic cell killing capacity of the parental virus in TRAIL-R2 expressing cancer cell lines by inducing apoptosis.Experiments in both hepatic carcinoma and malignant melanoma-bearing mice demonstrated that expression of either of IL-2 and TRAIL significantly inhibited the tumor growth compared to the intrinsic antitumor ability of the parental NDV virus and prolonged the survival of the tumor-bearing mice.Dual expression of both IL-2 and TRAIL further enhanced the antitumor potency of the parental NDV virus and further prolonged the survival of treated animals compared to either of the single gene expression in both tumor models.To understand the molecular basis of the antitumor mechanism of these recombinant viruses, we demonstrated that either rNDV-IL-2 or rNDV-IL-2-TRAIL-infected tumor cells in both xenograph models expressed IL-2, and either rNDV-TRAIL or rNDV-IL-2-TRAIL-infected tumor cells in both models expressed TRAIL.Either rNDV-IL-2 or rNDV-IL-2-TRAIL induced proliferation of the CD4+ and CD8+ populations in treated mice and elicited expression of series of antitumor cytokines, such as TNF-α, IFN-αt, IFN-β and IFN-γ.Tumor challenging experiments demonstrate that rNDV-IL2-TRAIL evolves mice a unique capacity to remember a pathogen through the generation of memory T cells, which rapidly protect the host in the event of reinfection and form adaptive immune system.Conclusions: The inherent antineoplastic and immune stimulatory properties of NDV could be further augmented by the introduction of immune IL-2 and therapeutic TRAIL genes, whose products initiates a broad cascade of immunological affects and induce tumor cells apoptosis in the microenvironment of the immune system.