Exotic mushrooms have been used in ancient Chinese medicine due to their immunomodulatory properties for the treatment and/or prevention of chronic diseases. However, only limited data exist on the health benefits of white button mushrooms (WBM), the most common in the American diet. In the current study, we investigated the effects of WBM and shiitake mushrooms (SM) on collagen-induced arthritis (CIA) using a 2 x 3 factorial design in 8-wk-old female dilute brown non-agouti mice that were fed a control diet (n = 37) or the same diet supplemented with 5% lyophilized WBM or SM (n = 27) for 6 wk. CIA was induced by immunizing mice with 100 µg bovine collagen followed by 50 µg LPS on d 20 post-collagen injection. CIA was assessed by mononuclear cell infiltration, bone erosion, plasma IL-6, TNFα, and intercellular adhesion molecule-1 (sICAM-1) concentrations. Compared with the control diet, WBM and SM tended to reduce the CIA index from 5.11 ± 0.82 to 3.15 ± 0.95 (P = 0.06) (median, 6-9 to 1-2) 31 d post-collagen injection. Whereas 58% of control mice had a CIA index ≥ 7, only 23% of WBM and 29% of SM mice did (P = 0.1). Although both types of mushrooms reduced plasma TNFα (34%, WBM; 64%, SM), only SM increased plasma IL-6 by 1.3-fold (P < 0.05). The CIA index was positively correlated with sICAM1 (r = 0.55; P < 0.05) but negatively correlated with TNFα (r = 0.34; P < 0.05). Whether mushrooms are beneficial for arthritis management remains to be investigated. To our knowledge, this is the first report demonstrating a possible health benefit of WBM in arthritis treatment.