This study evaluated the immunomodulatory and antitumor effects of a diet supplemented with Ganoderma lucidum (Ling Zhi or Reishi) medicinal mushroom mycelium obtained by solid-state fermentation. Over 14 weeks, animals from a test group were fed with 2 concentrations of G. lucidum mycelium, at 85% or 50%, labeled G85 and G50 diets, respectively. A control group received a regular diet. In the tenth week, half the animals from the test group and half the animals from the control group were inoculated with a suspension of Sarcoma 180 cells. Saline was injected in the remaining animals. In week 14, plasma levels of cytokines and the population of CD3(+), CD4(+), CD8(+), CD19(+), and CD16(+)/CD32(+) cells were evaluated. When compared to the control group, G. lucidum-supplemented diets altered the immune systems of the mice significantly (p < 0.05) the G50 diet proving more effective than the G85 diet. Mice inoculated with saline and fed with the G50 diet presented an increase in CD19(+) and CD16(+)/CD32(+) cell populations, along with an elevation in the tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma concentrations. Conversely, tumor-bearing mice fed with the G50 diet (labeled the G50-S group) presented an increase in CD3(+), CD4(+), and CD8(+) cells, but a decrease in CD19(+) and CD16(+)/CD32(+) cell populations. TNF-alpha and IFN-gamma concentrations were reduced in the G50-S group. The G50-S group presented a tumor weight 84% lower than that found in the control group. These results suggest that the immunomodulatory effect provoked by the consumption of G. lucidum mycelium possibly increased mice resistance against Sarcoma 180.