It was hypothesized that histone deacetylase (HDAC) inhibitors may increase survival after total-body irradiation (TBI) based on previous reports demonstrating that HDAC inhibitors stimulate the proliferation of bone marrow stem cells. Using the time for mice to lose 20% or more of their weight as the end point, two HDAC inhibitors, valproic acid and trichostatin-A, were found to reduce lethality in a dose-dependent manner. HDAC inhibitors were effective at reducing lethality when given either 24 h before or 1 h after TBI. The results indicate that HDAC inhibitors have potential for protecting against and mitigating radiation-induced lethality.