Objective To study the relationship between Caspase-12 expression and the hyperoxia-induced corpus callosum damage. Methods A total of 12 groups of C57 / BL6 mice were randomly assigned into hyperoxia group (80% O2 ) and control group (21% O2 ) at day 6 after birth (P6). The pups were sacrificed after 24 h and 48 h of hyperoxia exposure and at P10, P12, P15 and P30. Immunohistochemical ( IHC) method was used to detect the expression of myelin basic protein (MBP) in corpus callosum. Real-time PCR, Western Blot and IHC were used to detect the expression of mRNA and protein of Caspase-12 in corpus callosum. The corpus callosum apoptosis was measured using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling ( TUNEL ) method. Results The expression of MBP in hyperoxia group were significantly lower than the control group at P10 and P12 (P = 0. 004 and 0. 016); however, no significant differences existed between the two groups at P15 and P30 (P > 0. 05). The expression of Caspase-12 mRNA after 24 h and 48 h hyperoxia exposure were significantly higher than the control group [24 h: (1. 549 ± 0. 098) vs. (1. 080 ± 0. 101); 48 h:(1. 333 ± 0. 076) vs. (1. 022 ± 0. 089); P < 0. 05]. The expression of cleaved Caspase-12 protein after 24 h and 48 h hyperoxia exposure were also significantly higher than the control group [24 h: (1. 582 ± 0. 010) vs. (0. 994 ± 0. 078); 48 h: (1. 370 ± 0. 095) vs. (0. 978 ± 0. 069); P < 0. 05] . The Caspase-12 positive cell were significantly increased after 24 h and 48 h hyperoxia exposure comparing with the control group. The apoptosis index in hyperoxia group was significantly higher than the control group at P10 and P12 [P10: (18. 742 ± 2. 503) vs. (4. 587 ± 2. 353); P12 (36. 184 ± 3. 655) vs. (5. 351 ± 2. 678); P < 0. 05]. Conclusions Hyperoxia exposure induces corpus callosum damage in newborn mice. Over-expressed Caspase-12 may induce corpus callosum cell apoptosis excessively.