Natural killer (NK) cell cytotoxicity is an effective defense against metastatic tumor cells or viruses in the blood. However, NK cytotoxicity against tumor cells may be inhibited by a fibrinogen coat adhered to the surface of tumor cells. Ganoderma lucidum (G. lucidum) polysaccharides have been reported for their inhibitory ability on the adhesion of type I collagen, hyaluronan, fibronectin and laminin to integrins that were highly expressed on melanoma cells, and were therefore capable of enhancing NK cytotoxicity to tumor cells. In this study, we investigated the effect of G. lucidum polysaccharides on fibrinogen's adhesion to melanoma cells and NK cytotoxicity to tumor cells. Melanoma cells B16 and A375 were cultured and analyzed using flow cytometry. Human NK cells were isolated and analyzed using an NK cytotoxic assay. The results showed that polysaccharides extracted from G. lucidum inhibit the adhesion of fibrinogen to melanoma cells, and reverse the blocking effect of the fibrin coat on NK cytotoxicity against melanoma cells.