• Plant resistance to pathogen attack is often associated with a localized programmed cell death called hypersensitive response (HR). How this cell death is controlled remains largely unknown. • Upon treatment with cryptogein, an elicitor of tobacco defence and cell death, we identified NtHD2a and NtHD2b, two redundant isoforms of type-2 nuclear histone deacetylases (HDACs). These HDACs are phosphorylated after a few minutes' treatment, and their rate of mRNAs are rapidly and strongly reduced, leading to a 40-fold decrease after 10 h of treatment. • By using HDAC inhibitors, RNAi- and overexpression-based approaches, we showed that HDACs, and especially NtHD2a/b, act as inhibitors of cryptogein-induced cell death. Moreover, in NtHD2a/b-silenced plants, infiltration with cryptogein led to HR-like symptoms in distal leaves. • Taken together, these results show for the first time that type-2 HDACs, which are specific to plants, act as negative regulators of elicitor-induced cell death in tobacco (Nicotiana tabacum), suggesting that the HR is controlled by post-translational modifications including (de)acetylation of nuclear proteins.