Objective: Elevated myeloid-derived suppressor cells (MDSCs) in many malignancies are associated with the increased risk for metastases and poor prognosis. Therefore, a mouse model of intraocular melanoma was established to explore how MDSCs influence liver metastases. Methods: In this study, murine B16LS melanoma cells were transplanted into the posterior compartment (PC) of the eye of C57BL/6 mice. Leucocytes from the liver of naive mice and mice bearing melanoma liver metastasis were isolated using isotonic Percoll centrifugation, examined by flow cytometry for their expression of Gr1, CD11b, F4/80, RAE-1, and Mult-1, and further isolated for MDSCs and natural killer (NK) cells. The effects of MDSCs on NK cells were tested by coculturing and assessing the ability of NK cells to produce interferon-gamma (IFN-gamma) by ELISA and NK cell cytotoxicity by 3H-thymidine incorporation assay. The impact of IFN-gamma on liver metastases was examined via selectively depleting IFN-gamma in vivo. Results: The results showed that mice with liver metastases had increased levels of CD11b(+)Gr1(+)F4/80(+) as well as CD11b+Gr1+F4/80- MDSCs. MDSCs significantly enhanced the generation of IFN-gamma together with the cytotoxicity of the NK cells. Furthermore, these effects were cell-cell contact-dependent. Although IFN-gamma was not of a toxic nature to the melanoma cells, it profoundly inhibited B16LS cell proliferation. Depleting IFN-gamma in vivo led to increased liver metastases. Conclusion: All these findings first revealed that MDSCs accumulated in liver metastasis of intraocular melanoma could activate the NK cells to produce an effective anti-tumor immune response. Thus, the MDSCs' performance in different tumor models would need more investigation to boost current immunotherapy modalities.