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Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. NF-κB transcription factor family is activated by two main pathways, the canonical and the alternative NF-κB activation pathways with different functions. The alternative NF-κB pathway leads to the activation of the transcriptionally active RelB NF-κB subunit. Alternative NF-kB activation status and its role in DLBCL pathogenesis remain undefined. Here, we reveal a frequent activation of RelB in a large cohort of DLBCL patients and cell lines, independently of their ABC or GCB subtypes. RelB activity defines a new subset of DLBCL patients with a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for ABC tumors carrying MYD88L265Pand CD79B mutations that cooperatively activate canonical NF-κB, thus indicating that current genetic tools to evaluate NF-κB activity in DLBCL do not provide information on the alternative NF-κB activation. Further, the newly defined RelB-positive subgroup of DLBCL patients exhibits a dismal outcome following immunochemotherapy. Functional studies revealed that RelB confers DLBCL cell resistance to DNA-damage induced apoptosis in response to doxorubicin, a genotoxic agent used in front-line treatment for DLBCL. We also show that RelB positivity is associated with high expression of cIAP2. Altogether, RelB activation can be used to refine the prognostic stratification of DLBCL and may contribute to subvert the therapeutic DNA damage response in a segment of DLBCL patients.