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Objective To compare the difference of biscyclohexanone oxaldihydrazone (cuprizone)-induced demyelination in female and male mice. Methods Ten male mice and 10 female mice were selected and fed with 0.2% cuprizone for 6 weeks in order to establish the demyelination model. Rotarod test was used to examining motor function of balance and coordination. Luxol fast blue-periodic acid Schiff (LFB-PAS) staining was used to examine the area of demyelination in corpus callosum. The fluorescence intensity of myelin base protein (MBP) in corpus callosum was examined by immunohistochemistry with antibody of MBP. Western blotting was performed to examining the levels of MBP in the brain tissues. Results In the female mice (female group), the running time was (117.60 ± 18.48) s, the times of falling off were 3. 2 ±0. 8, the myelination scores were 2. 20 ± 0. 27, the intensity of MBP was 65. 20 ± 6. 46 and the expression of MBP was 0. 44 ± 0. 06; and those indexes in the male mice (male group) were (90. 80 ± 8. 70) s, 4. 6 ± 0. 9, 1. 70 ± 0. 27, 47. 31± 5. 79, and 0. 27 ± 0. 05. Compared with the female group, the running time was shorter, the times of falling off were more, the myelination score was lower, MBP intensity was lower, and the relative expression of MBP was lower in the male group (all P<0.05). Conclusion In the cuprizone-induced demyelination models, the male mice are more easily to demyelination than the female mice. [ABSTRACT FROM AUTHOR]