Medicinal mushrooms are used in popular medicine largely as health promoters, mainly because of their antitumor and immunomodulatory activities. Ganoderma lucidum (lingzhi or reishi) and Agaricus brasiliensis are mushrooms that have long been used for medicinal purposes. This study evaluated their immunomodulatory and antitumor effects on mice fed a diet supplemented with G. lucidum and A. brasiliensis mycelia obtained from solid-state fermentation. For 14 weeks the mice were fed chow containing 50% A. brasiliensis and G. lucidum mycelia, using ground wheat as an excipient. The consumption of the supplemented diet inhibited Sarcoma 180 tumor growth and caused important changes in the immune system. The pattern of immune response shifted, increasing CD4+ and CD8+ and decreasing CD19+ cell populations. The restoration of a proper balance between cellular and humoral immunity is an essential process for restraining tumor growth. These results suggest that polysaccharides, such as β-glucans and other mushroom metabolites, possibly promote the T-cell dominance that is imperative to restrain tumor growth.