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.