Metastasis to distal organ is a fatal cause of cancer death and liver is one of the most common site of metastasis leading to poor prognosis. Although it has been known that innate immune cells play critical roles in the regulation of liver metastasis, how they control the tumor development is still largely unclear. Here, we found that Dectin-2, a C-type lectin receptor (CLR) essential for anti-fungal innate immunity, is required for the suppression of liver metastasis in vivo. Such anti-tumor system was not triggered in subcutaneous tumor growth and lung metastasis, indicating the liver-selective function of Dectn-2. Analysis for the mechanism revealed that Dectin-2-mediated tumor rejection required Kupffer cells, liver-residing macrophages, which express Dectin-2 dominantly in liver. Moreover, Dectin-2 enhanced the uptake and clearance of cancer cells by Kupffer cells. Interestingly, Kupffer cells are uniquely endowed with Dectin-2-dependent phagocytotic function, as neither bone marrow-derived macrophages nor alveolar macrophages show such phenotype. We further examined the involvement of other CLRs in Dectin-2-regulated anti-tumor responses and found that macrophage C-type lectin (MCL), a CLR known for forming complex with Dectin-2, also contributed to the uptake of cancer cells by Kupffer cells and the rejection of liver-metastasizing cells. Another CLR Dectin-1 suppressed liver metastasis as well, however, the engulfment of cancer cells by Kupffer cells was not regulated by Dectin-1. Instead, Dectin-1 promoted the anti-tumor cytotoxicity of liver non-parenchymal cells, which is mostly mediated by natural killer cells. Dectin-2 and MCL were not involved in such host killing machinery against tumor cells. Collectively, these results indicate that Dectin-2 selectively suppresses liver metastasis through the enhancement of cancer cell engulfment by Kupffer cell, in cooperation with MCL and distinctly from Dectin-1. This study provides the promising insights for the development of novel anti-cancer therapy targeting CLRs.