Inhibitors of histone deacetylases, including suberoylanilide hydroxamic acid (SAHA) and Trichostatin A (TSA), are emerging anticancer agents. In the current study, we have examined the cytoprotective effects of these agents. Cisplatin induced 40-50% apoptosis in rat kidney proximal tubular cells (RPTC) in 18 hours, which was suppressed to 20-30% by 1-5 μM SAHA or 0.1 μM TSA. Consistently, SAHA partially prevented cisplatin-induced caspase activation. The cytoprotective effects of SAHA and TSA were associated with long term cell survival. During cisplatin treatment, Bax translocated to mitochondria, leading to cytochrome c release. Both Bax translocation and cytochrome c release were ameliorated by SAHA. Mechanistically, SAHA inhibited and TSA delayed p53 phosphorylation, acetylation and activation during cisplatin incubation. At the upstream signaling level, SAHA blocked cisplatin-induced phosphorylation of Chk2, a key DNA damage response kinase. Interestingly, in HCT116 colon cancer cells SAHA suppressed cisplatin-induced p53 activation, but enhanced apoptosis. The results suggest that inhibitors of histone deacetylases can protect against cisplatin nephrotoxicity by attenuating DNA damage response and associated p53 activation.