Natural Killer (NK) cells mount a fast and efficient immune response against tumor cells and are currently a major focus in the development of anti-cancer cell-based therapies. Due to major differences between the murine and human NK cell receptor system, a non-human primate model would be helpful to evaluate the efficiency of NK-cell based therapies prior to clinical applications. In humans, B7-H6 has been shown to facilitate the elimination of lymphoma cells through the interaction with its receptor NKp30. The common marmoset (Callithrix jacchus) is a new world monkey readily used in biomedical research due to its easy management and proximity to humans. In this study, we demonstrated the expression of B7-H6 antigen in marmoset B-lymphoblastoid cell lines. In addition, a method was established to isolate B- or NK-cells from peripheral blood of marmosets with purities of up to 97%We detected the expression of B7-H6 in lymphoma cells and for the first time in leukemic blasts of human acute myeloid leukemia (AML). Marmoset NK cells were shown to lyse marmoset B lymphoblastoid cell line (B-LCL) cells by up to 28.4% and human B-LCL cells by up to 20%. This effect was abrogated when the NK cells were pre-treated with an anti-NKp30 specific antibody. Also, marmoset NK cells were able to lyse primary leukemic AML cells and lymphoma cells by up to 8.3 and 20.3%respectively. Stimulation of marmoset NK cells with recombinant B7-H6 induced phosphorylation of ERK1/2 and proliferation rates. Furthermore, the secretion of IL-1β, IL-8, IFN-γ and TNF-α was significantly increased upon B7-H6 stimulation. In conclusion, we demonstrated that non-human primate NK cells have similar mechanisms for the lysis of tumor cells as human NK cells. Thus, this animal model constitutes a very promising tool for the development and evaluation of novel NK-cell based therapies.