Here, we used venetoclax to study the effect of BCL2 inhibition on B-cell and T-cell populations within the tumor microenvironment (TME) of DEL-DLBCL mouse models and evaluated whether venetoclax could be efficiently combined with anti-CD20-based immunotherapy to improve long-term control of MYC/BCL2 co-expressing DLBCL....DEL-DLBCL mice were refractory to venetoclax alone, inhibition of BCL2 significantly extended overall survival of mice that were simultaneously treated with a murine surrogate for anti-CD20 rituximab....These results suggest that the combination of anti-CD20-based immunotherapy and BCL2 inhibition leads to cooperative immunomodulatory effects and improved preclinical responses, which may offer promising therapeutic opportunities for DEL-DLBCL patients.