We attempted to explore novel treatment options for progressive diffuse large B-cell lymphoma (DLBCL) with TP53 mutation that has a poor response to rituximab-based immunochemotherapy. Herein, we report the case of a patient with DLBCL having TP53 mutation who showed progression following four cycles of rituximab-based immunochemotherapy but achieved sustained partial remission following chidamide-based chemotherapy. In vitro experiments performed using the DLBCL cell lines OCI-ly1 (LY1; mutant TP53), OCI-ly10 (LY10; wild-type TP53) and OCI-ly19 (LY19, wild-type TP53) demonstrated that chidamide is more potent against cells with mutant TP53 mutant than those with wild-type TP53. Moreover, chidamide can reduce the mRNA and protein expression levels of mutant TP53 and upregulate the surface expression of the CD20 antigen in lymphoma cells.Keywords: mutation; CD20; chidamide; diffuse large B-cell lymphoma; immunochemotherapy; immunomodulator; thalidomide.