Computational models of traumatic brain injury (TBI) can predict injury-induced brain deformation. However, predicting the biological consequences (i.e. cell death or dysfunction) of induced brain deformation requires tolerance criteria. Here, we present a tolerance criterion for the cortex which exhibits important differences from that of the hippocampus. Organotypic slice cultures of the rat cortex, which maintain tissue architecture and cell content consistent with that in vivo , were mechanically injured with an in vitro model described previously. Cultures were stretched equibiaxially up to 0.35 Lagrangian strain at strain rates up to 50 s −1 . Cell death was quantified at 1, 2, 3, and 4 days following injury. Statistical analysis (repeated measures ANOVA) showed that all three factors (Strain, Strain Rate, and Time post-injury) significantly affected cell death. An equation describing cell death as a function of the significant parameters was then fit to the data. Compared to the hippocampus, the cortex was less vulnerable to stretch-induced injury and demonstrated a strain threshold below 0.20. Strain rate was also a significant factor for cortical but not hippocampal cell death. Cortical cell death began at an earlier time point than in the hippocampus, with cell death evident at 1 day post-injury versus 3 days in the hippocampus. In conclusion, different regions of the brain respond differently to identical mechanical stimuli, and this difference should be incorporated into finite element models of TBI if they are to more accurately predict in vivo consequences of TBI.