Mushroom contains a wide variety of components with high immune-modulating properties. Mushroom polysaccharides are known as immunocorrectors with wide areas of usage, which balance the immune system without resulting in the entire immune suppression or overreaction. To explore the potentially immunomodulatory role of Climacodon pulcherrimus, the present study was intended to evaluate the in vitro immunomodulatory activity of C. pulcherrimus polysaccharides (CPP) on rat neutrophils and macrophages. CPP was studied on lipopolysaccharide-induced neutrophils and macrophages' responses. The effect on phagocytosis, release of reactive oxygen intermediates (ROI), nitric oxide (NO), lysosomal enzyme release and neutrophil myeloperoxidase, and neutrophil adherence was assessed. The cytotoxicity of CPP against macrophages using 3-(4,5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide assay and neutral red inclusion assay was also assessed. ENPC (endopolysaccharides) markedly enhanced phagocytosis of macrophages and neutrophils, whereas the EXPC (exopolysaccharides) increased only that of neutrophils at 0.34 and 0.68 mg/mL. The production of NO evidently increased in ENPC- and EXPC-treated neutrophil and macrophage cultures. The production of ROI in a concentration-dependent manner increased in ENPC-treated (0.08-5.55 mg/mL) and EXPC-treated (0.17 and 0.34 mg/mL) macrophage cultures and ENPC-treated neutrophils, whereas it decreased in EXPC-treated neutrophils. The secretion of acid phosphatase increased in ENPC- and EXPC-treated macrophage and neutrophil cultures. Neutrophil myeloperoxidase release increased in EXPC-treated (5.55 mg/mL) cultures, whereas it decreased in ENPC-treated cultures. ENPC and EXPC increased the adhesion of neutrophils to microplate. These findings demonstrated that CPP displayed a dual mode of action, inhibiting or enhancing numerous phagocytic activities of macrophages and neutrophils.