Objective To investigate the effects of nuclear factor kappa B activator 1(Act1) on lung metastasis ofmelanoma in mice. Methods Mice were genetically engineered to enable the targeted suppression of Act1 in macrophages(anti-Act1). The lung metastasis model was generated by tail vein injection of B16-F10 melanoma cells. The extent of lungmetastasis was assessed pathology using HE staining of lung tissues. The infiltration of CD45+ leukocytes and CD68+macrophages and the proliferation index of tumor cells in lung tissues were evaluated by immunohistochemistry. Results The anti-Act1 mice developed fewer metastatic and micro-metastatic foci, with reduced CD45+ leukocyte and CD68+macrophage infiltration in the lung tissues, when compared with the C57 control mice. Cells of metastatic and micrometastaticfoci in the anti-Act1 mice demonstrated a reduced proliferation index, when compared with those of control animals. Conclusions Targeted suppression of Act1 in macrophages inhibits the lung metastasis of murine melanoma.