Anaplastic diffuse large B-cell lymphoma (A-DLBCL) is a rare morphologic variant characterized by the presence of polygonal, bizarre-shaped tumor cells. However, the clinicopathologic and genetic features of this variant are largely unknown. In this study, we investigated 35 cases of A-DLBCL with regard to their clinical, pathologic, and genetic characteristics. The age of the patients ranged from 23 to 89 years (median age, 62 y) with a male to female ratio of 23:12. Twenty-two of 26 (85%) patients had Ann Arbor stage III or IV disease, and 17/26 (65%) patients had a high-intermediate or high International Prognostic Index score. For the 24 patients treated with aggressive chemotherapy regimens, the median overall survival (OS) was 16 months, and the 2-year OS rate was 36%. Immunophenotypically, 30/35 (86%) cases had a non-germinal center B-cell immunophenotype. CD30 expression was present in 18/35 (51%) cases, and the p53 protein stain was positive in 28/35 (80%) cases. Fifteen of 35 (43%) cases expressed both BCL2 and MYC (double expressor). Twenty-nine of 32 (91%) cases tested positive for RELA, RELB, or c-Rel in the nucleus, indicating activation of the NFκB signaling pathway. Cytogenetically, 11/27 (41%) cases had concurrent MYC and BCL2 and/or BCL6 abnormalities (translocation or extra copy), including 5 cases with triple abnormalities. TP53 mutation was found in 17/30 (57%) cases, whereas the MYD88 L265P, CD79B, and CARD11 mutations were found in 7/35, 4/30, and 5/30 cases, respectively. We compared the A-DLBCL group with 50 patients with DLBCL without anaplastic features (common DLBCL). The OS of patients with A-DLBCL was significantly worse than that of patients with DLBCL without anaplastic features (P=0.004). Cases of A-DLBCL more often had a high International Prognostic Index score and a non-germinal center B-cell immunophenotype, more frequently expressed CD30 and p53, and more often had mutations of TP53 and concurrent abnormalities of MYC and BCL2 and/or BCL6 (P<0.05). In conclusion, A-DLBCL displays clinicopathologic features that distinguish it from ordinary DLBCL. Most patients follow an aggressive clinical course and have a poor outcome. Cases of A-DLBCL have a high frequency of TP53 mutation and genetic abnormalities of MYC, BCL2, and BCL6.