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Background and Aim: Ganoderma Lucidum has been regarded as a natural immunomodulator. The exact carbohydrate epitope responsible for the immunomodulatory activity and its receptor have not been identified, but it seems likely that it is the receptor CR3 (complement receptor 3) which can bind to β-glucan polysachharide. Because glucose-6-phosphate dehydrogenase (G6PD) activity has a critical role in the regulation of macrophage functions such as nitric oxide (NO) production, we assessed the immunomodulatory effect of GL-PS in BALB/c peritoneal macrophages. Materials and Methods: For this purpose, BALB/c mice peritoneal macrophages were isolated and treated with various concentrations of GL-PS (0.001, 0.01, 0.1, 1, 10, 100 g/ml). After 24 hours, the viability of treated macrophages was measured by MTT assay at 540 nm and the effective dose was determined to be 0.1µg/ml. Then, macrophages were sonicated and special activity of G6PD was measured in the cell extracts by measuring the alterations in NADPH absorption at 339nm and protein concentration by Bradford method. Also, NO production was determined by use of Griess-reagent after 18 hours. Results: Results of this study showed that 0.1 g/ ml of GL-PS had the maximal effect on cell viability (stimulation Index) in comparison to other doses )0.05p(. Conclusion: Ganoderma Lucidum is widely used in traditional Chinese medicine to improve quality and length of life. We concluded that GL-PS extract had an immunomodulatory effect on macrophage functions. So, it can be a good choice to augment phagocytic system against infectious agents and pathogens such as Leishmania species, because nitric oxide production plays a critical role against these organisms.