Post-transplantation lymphoproliferative disorder is an aggressive complication of transplantation, most frequently of diffuse large B-cell lymphoma morphology and associated with Epstein-Barr virus (EBV) infection/reactivation. In this study the microenvironment of EBV(+) (n=23) and EBV(-) (n=9) post-transplant non-germinal center B-cell diffuse large B-cell lymphoma was characterized. Of EBV(+) cases somatic hypermutation analysis, gene expression profiling, and extensive phenotyping were performed. Our results demonstrated variable cytotoxic T-cell infiltration and significantly increased CD163(+) M2 macrophage infiltration in EBV(+) compared with EBV(-) post-transplant diffuse large B-cell lymphoma. On the basis of IgM staining and hypermutation analysis, two EBV(+) post-transplant diffuse large B-cell lymphoma subgroups were identified: IgM(+) tumors lacking somatic hypermutations and IgM(-) tumors harboring somatic hypermutations. IgM(-) tumors arose late following transplantation (median interval: 16 months), mainly in kidney recipients. IgM(+) tumors on the other hand arose early (median interval: 3 months, P-value=0.0032), almost exclusively following stem cell transplantation and were associated with worse outcome (median survival 1 month for IgM(+) versus 41 months for IgM(-) tumors, log-rank/Wilcoxon P-value 0.07/0.04). Notably, IgM(+) tumors were characterized by plasma cell features (monotypic kappa/lambda expression, high MUM1 expression, and partial CD138 expression) and a high proliferation index. Consistent with the plasma cell phenotype, unfolded protein response signaling was upregulated. In contrast, IgM(-) EBV(+) post-transplant diffuse large B-cell lymphoma did not express kappa, lambda, IgD, or CD138 and expressed limited MUM1. In these tumors T-cell signaling was enhanced associated with increased T-cell infiltration compared with IgM(+) cases. Overall, our results allow further molecular classification of EBV(+) post-transplant diffuse large B-cell lymphoma and provide a rationale for the use of subtype-specific-targeted therapies (eg, bortezomib in IgM(+) tumors). Our findings also provide a biological basis for the clinical differences between post-transplant lymphoproliferative disorder following solid organ and stem cell transplantation, which are regarded as different disorders.