AbstractPurposeLarge B‐cell lymphoma withIRF4rearrangement (LBCL,IRF4+) has been recently recognized as a specific entity that is frequently associated with young age and favorable prognosis. However, whether the good outcome of the disease is due toIRF4+ or other factors remains obscure. We thus analyzed 100 young patients with primary head and neck LBCL to see the clinicopathologic correlates ofIRF4+.MethodsThe histopathology, immunophenotype,IRF4status of the tumors, and clinical data were reviewed.ResultsTwenty‐one tumors were diagnosed as LBCL,IRF4+, which were more frequently associated with a follicular growth pattern, medium‐sized blastoid cytology, germinal center B‐cell‐like, and CD5+ phenotype, compared with IRF4− ones. While most of the patients received chemotherapy with or without radiation, eightIRF4+ patients received mere surgical resection of the tumor and exhibited excellent outcome.IRF4+ cases featured a significantly higher complete remission rate, and better survivals compared withIRF4− ones. Multivariate analysis confirmedIRF4+ correlates with a better survival.ConclusionOur work confirmed the unique clinicopathologic features of LBCL,IRF4+, and disclosed for the first time the independent favorable prognostic impact ofIRF4+. These findings may further unravel the heterogeneity of LBCL occurring in youth, and aid in risk stratification and tailoring the therapeutic strategy.