BACKGROUND: Yishendaluo decoction reduces production of inflammatory mediators, relieves damage due to inflammatory reactions, and improves neural functions during experimental autoimmune encephalomyelitis. OBJECTIVE: To investigate the effects of Yishendaluo decoction on a mouse model of experimental autoimmune encephalomyelitis. DESIGN, TIME AND SETTING: The randomized, controlled, neuropathological, and molecular biological animal study was performed at the Key Laboratory of Chinese Internal Medicine, Ministry of Education, Dongzhimen Hospital of Beijing University of Chinese Medicine and Center for Neuroinformatics, General Hospital of Chinese PLA from 2005 to 2006. MATERIALS: Yishendaluo decoction pieces consisting of prepared rehmannia root, colla cornus cervi, cape jasmine fruit, and grassleaf sweetflag rhizome were purchased from the Dongzhimen Hospital of Beijing University of Chinese Medicine. Rabbit anti-mouse β-amyloid precursor protein and p38 polyclonal antibody (Zhongshan Goldenbridge Biotechnology, China), as well interferon-γ and interleukin-4 ELISA kit (Boster, China), were used in this study. METHODS: A total of 96 healthy, female, SJL/J mice, aged 8-12 weeks, were equally and randomly assigned to normal, model, hormone, and Chinese medicine groups. A total of 0.2 mL antigen preparation, supplemented with 150 μg PLP139-151 and 400 μg H37RA, was subcutaneously injected into the upper abdomen of mice from the model, hormone, and Chinese medicine groups. Mouse models of experimental autoimmune encephalomyelitis were established by intravenous injection of 0.1 mL Bordetella pertussis solution containing 0.6 × 10~6 Bordetella pertussis at days 1 and 3. Mice from the model, Chinese medicine, and hormone groups were respectively subjected to 0.2 mL saline, 2 g/kg Yishendaluo decoction, and 0.078 mg/kg prednisone acetate, once daily for 14 consecutive days. Mice from the normal group were left intact. MAIN OUTCOME MEASURES: Pathological changes were observed using hematoxylin-eosin staining and Luxol fast blue staining. Expression of β-amyloid precursor protein and p38 protein was determined by immunohistochemistry. Levels of interferon-γ and interleukin-4 were detected by ELISA. Behavioral changes were assessed in mice according to scores of neurological function. RESULTS: A few inflammatory cell infiltration, nerve fiber breakage and slight demyelination were detected in the central nervous system of mice from the Chinese medicine and hormone groups compared with the model group. Expression of β-amyloid precursor protein and p38 protein was significantly diminished in the central nervous system of mice from the Chinese medicine and hormone groups compared with the model group (P < 0.05 or P < 0.01), and the decrease was greatest in the Chinese medicine group. The decrease in mouse weight was not significant, and neurological function scores were less in the Chinese medicine and hormone groups compared with the model group (P < 0.05 or P < 0.01). Interferon-γ levels were significantly reduced (P < 0.01), and interleukin-4 levels were significantly increased (P < 0.01) in the brains of the Chinese medicine and hormone groups, compared with the model group. CONCLUSION: Yishendaluo decoction improved neurological function in mice with experimental autoimmune encephalomyelitis by downregulating β-amyloid precursor protein expression, resisting axonal degeneration, and relieving inflammatory reaction. The anti-inflammatory mechanism was regulated by inhibition of the p38 mitogen-activated protein kinase signal pathway.