Volvaria volvacea (Bull. ex Fr.) Sing, an important edible and medicinal macro-fungus, has been used to remedy various diseases for hundreds of years in East Asia. To identify key proteins with the unique therapeutic activity in V. volvacea, we conducted a genomewide comparison of V. volvacea protein families and those of other edible fungi that lack therapeutic functions and identified seven fungal immunomodulatory proteins (FIPs) in V. volvacea. On the basis of the predicted physiological and biochemical characteristics of the seven FIPs, the novel Fip-vvo82 was inferred to have high immunomodulatory activity; this was confirmed by molecular and immunological experiments and further characterized by modeling the three-dimensional structure and protein-protein docking. This is the first study to show that V. volvacea has more than one FIP.