Significant injury during bacterial meningitis arises from mechanisms of neuronal apoptosis, particularly in the hippocampus. Apoptosis can involve both the caspase-dependent and the caspase-independent pathway, and, although both pathways have been implicated in pneumococcus-induced neuronal cell death, their relative contributions in vivo are unclear. We used mice deficient in the activation of caspase-3, ATM, and p53 to examine the role that caspase-dependent apoptosis plays in neuronal death in the context of pneumococcal meningitis. The overall symptomatology of acute infection was similar in all mice tested, indicating that late sequelae are the clinical manifestations of neuronal death. Two phases of apoptosis were discernible: neuronal injury at 18 h after infection was independent of the caspase-3 pathway, and neuronal cell death at 24 h after infection was attenuated in the absence of the caspase-3 pathway. We conclude that treatments to increase the survival rate of neurons in patients with meningitis will need to take into account at least these 2 mechanisms of damage.