Objective To evaluate the efficacy and safety of glofitamab as a later-line salvage therapy in patients with high-grade B-cell lymphoma (HGBL) harboring C-myc/BCL2/BCL6 rearrangements.Methods Using a case report integrated with literature analysis, we analyzed a 55-year-old female HGBL patient with C-myc/BCL2/BCL6 rearrangements who received third-line glofitamab (CD20×CD3 bispecific antibody).Results The patient underwent sequential frontline therapy consisting of an R-CHOP-like regimen followed by Pola-R-CHP for four cycles before developing disease progression. Second-line therapy with R-DICE-like plus selinexor failed to achieve objective response. Given high tumor burden and suboptimal response to conventional chemotherapy, glofitamab was administered as third-line therapy, achieving partial response after three treatment cycles. Following initial glofitamab infusion, grade 2 cytokine release syndrome manifested with high fever, which was managed by tocilizumab after dynamic monitoring of lymphocyte subsets and cytokine levels.Conclusion Glofitamab may provide clinical benefits in multi-drug resistant HGBL as a salvage therapy, but requires vigilant adverse event monitoring with intensive clinical surveillance.