Traumatic brain injury (TBI) damages the hippocampus both in experimental animal models and in humans. In particular, the mechanical injury in combination with the genetic susceptibility to injury may result in neuronal loss from the hippocampus. This report explores the time-course of neuronal loss in the four primary subregions of the mouse hippocampus after a lateral fluid percussion injury (FPI) to the brain, and how subtle genetic differences between C57BL/6J and C57BL/10J mouse strains influence the extent and time course of neuronal loss. Using design-based stereological procedures, our results indicate negligible neuronal loss ipsilateral to the injury at 2 days postinjury in C57BL/6J mice, whereas a significant number (30-40%) of neurons are lost across all subregions of the hippocampus (dentate, hilus, area CA3, and area CA1) by 1 week, which does not appear to progress at 1 month, compared to sham. Additionally, neuronal counts after lateral FPI in a genetically similar, yet kainic acid-sensitive, mouse strain (C57BL/10J) showed no statistically significant differences in neuron number compared to the C57BL/6J strain in response to brain injury. Hippocampal neuronal loss after lateral FPI and its consequent circuit disruption may depend more on factors related to the mechanics and secondary consequences of the injury, as opposed to subtle genetic variations between inbred mouse strains. The loss of neurons appears to be restricted to the first week post-injury, and the remaining neurons may serve as a substrate for recovery.