Although p53 controls cell death after various stresses, its role in neuronal death after brain ischemia is poorly understood. To address this issue, we subjected p53-deficient (p53-/- and p53+/-) mice (backcrossed for 12 generations with C57BL/6 mice) and wild-type mice (p53+/+) to transient global ischemia by the three-vessel occlusion method. Despite similar severity of ischemia, as shown by anoxic depolarization and cortical blood flow, neuronal death in the hippocampal cornus ammonis (CA)1 region was much more extensive in p53+/+ than in p53-/- mice (surviving neuronal count, 9.3%+/-3.0% versus 61.3%+/-34.0% of nonischemic p53+/+ controls, respectively, P<0.0037). In p53+/- mice, a similar trend was also observed, though not statistically significant (43.5% of nonischemic p53+/+ controls). In p53+/+ mice, p53-like immunoreactivity in hippocampal CA1 neurons was enhanced at 12 h after ischemia, and messenger ribonucleic acid for Bax, a direct downstream target of p53, was also increased. These results indicate that p53 potentiates ischemic neuronal death in vivo and suggest that this molecule could be a therapeutic target in neuronal death after cerebral ischemia.