Genomic analysis identifies a unique pediatric subtype of EBV-negative primary CNS large B-cell lymphoma. Clinical, histologic, and genetic features of the 12 pediatric and young-adult patients with PCNS-LBCL, alongside 6 conventional cases of PCNS-LBCL occurring in older adults. Categorization into pediatric- and adult-type tumor groups was performed according to recurrent molecular alterations involving MYD88, PRDM1, CDKN2A/B, HLA gene cluster, NFKBIE, GNA13, and TP53.