Heterogeneous clinical responses to histone deacetylase inhibitors (HDACi) in diffuse large B-cell lymphoma (DLBCL) have prompted a need for evaluating the impact of mutations in the histone acetyl transferases (HAT) CREBBP and EP300 on HDACi treatment outcome. We identified four DLBCL cell lines; Toledo, with mutations in CREBBP and EP300 , SUDHL-7 with mutation of CREBBP and wild-type (wt) EP300 , RL with mutation of EP300 and wt CREBBP , and U2932 with wt CREBBP and wt EP300 . Vorinostat treatment induced apoptosis significantly more rapid and profound in the CREBBP/EP300 double mutant cell line. Our results suggest that pre-treatment stratification according to HAT defects may be relevant in DLBCL