Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive non-Hodgkin’s lymphoma, and 40% of patients succumb to death. Despite numerousclinical trials aimed at developing treatment strategies beyond the conven-tional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, andprednisone) regimen, there have been no positive results thus far. Although theselective BCL2 inhibitor venetoclax has shown remarkable efficacy in chronic lym-phocytic leukemia, its therapeutic effect in DLBCL was limited. We hypothesizedthat the limited therapeutic effect of venetoclax in DLBCL may be attributedto the complex expression and interactions of BCL2 family members, includingBCL2. Therefore, we aimed to comprehensively analyze the expression patternsof BCL2 family members in DLBCL. We analyzed 157 patients with de novoDLBCL diagnosed at Asan Medical Center and Ajou University Hospital. ThemRNA expression levels of BCL2 family members were quantified using theNanoString technology. BCL2 family members showed distinct heterogeneousexpression patterns both intra- and inter-patient. Using unsupervised hierarchi-cal cluster analysis, we were able to classify patients with similar BCL2 familyexpression pattern and select groups with clear prognostic features, C1 and C6.In the group with the best prognosis, C1, the expression of pro-apoptotic and pro-apoptotic BH3-only group gene expressions were increased, while anti-apoptoticgroup expression was significantly increased in both C1 and C6. Based on this, wegenerated the BCL2 signature score using the expression of pro-apoptotic genesBOK and BCL2L15, and anti-apoptotic gene BCL2. The BCL2 signature score0 had the best prognosis, score 1/2 had intermediate prognosis, and score 3 hadthe worst prognosis (EFS, p = 0.0054; OS, p = 0.0011). Multivariate analysis,including COO and IPI, showed that increase in the BCL2 signature score wassignificantly associated with poor prognosis for EFS, independent of COO andIPI. The BCL2 signature score we proposed in this study provides information onBCL2 family deregulation based on the equilibrium of pro- versus anti-apoptoticBCL2 family, which can aid in the development of new treatment strategies forDLBCL in the future.