Diffuse large B-cell lymphoma (DLBCL) includes the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, which differ in cell of origin, genetics, and clinical response. By screening the subtype-specific activity of 211 drugs approved or in active clinical development for other diseases, we identified inhibitors of nicotinamide phosphoribosyl transferase (NAMPTi) as active in a subset of GCB-DLBCL in vitro and in vivo. We validated three chemically distinct NAMPTis for their on-target activity based on biochemical and genetic rescue approaches and found the ratio between NAMPT and PARP1 RNA levels was predictive of NAMPTi sensitivity across DLBCL subtypes. Notably, the NAMPT:PARP1 transcript ratio predicts higher antitumor activity in BCL2-translocated GCB-DLBCL. Accordingly, pharmacologic and genetic inhibition of BCL2 was potently synergistic with NAMPT blockade. These data support the inhibition of NAMPT as a therapeutically relevant strategy for BCL2-translocated DLBCLs. Significance: Targeted therapies have emerged for the ABC subtype of DLBCL, but not for the GCB subtype, despite the evidence of a significant subset of high-risk cases. We identify a drug that specifically targets a subset of GCB-DLBCL and provide preclinical evidence for BCL2 translocations as biomarkers for their identification.