Diffuse large B-cell lymphoma (DLBCL) is a neoplasm affecting adults and children, with different clinical behaviors between age groups. To shed light on those differences, gene expression profiling was evaluated in 48 formalin-fixed paraffin-embedded biopsies of patients with DLBCL. Sixteen differentially expressed genes in pediatric DLBCL compared to adults were demonstrated, involving lymphocyte differentiation, oncogenic signaling and chemotaxis. Pathway analysis confirmed the enrichment in proliferation-related pathways. In addition, the increased presence of NKCD56dim cells in pediatric patients suggests a cytotoxic immune response in this group, perhaps explaining their better outcome. Exclusion of Epstein Barr virus (EBV) + DLBCL, NOS, showed, in pediatric cases, additional downregulated genes associated with immune regulators and checkpoint genes. This suggested EBV infection may have on the modulation of immune response in pediatric lymphomas. Survival analysis showed associations between genes such as MYC, NT5E and CD34, and event-free survival in pediatric patients. Furthermore, higher expression of MYC in children displayed higher risk of death or relapse, while lower expression of NT5E and CD34 was associated with lower risk. This study identifies distinct immune response and proliferation gene expression patterns in pediatric DLBCL compared to adults, and the interaction with tumor microenvironment, with potential implications for disease pathogenesis.