This study investigated the gene expression profiles of 40 cases of diffuse large B-cell lymphoma (DLBCL) according to CD21 expression, a favourable prognostic factor in DLBCL. Signature genes were analysed by Gene Ontology Tree Machine, and genes concerned with the immune system and related categories were significantly upregulated in CD21- DLBCLs. Of 40 DLBCLs, four were germinal centre B cell-like (GCB) and 36 non-GCB. Of the 36 non-GCB DLBCLs, 14 CD21+ DLBCLs showed significantly better overall survival than the 22 CD21- DLBCLs (P = 0.036). Hierarchical cluster analysis of signature genes related to CD21 was applied to previously published data sets, resulting in two groups for each data set, CD21+ type DLBCLs and CD21- type DLBCLs. Survival of CD21+ type DLBCLs was significantly better than that of CD21- type (P = 0.006 and P = 0.004, respectively). In both data sets, CD21+ type DLBCLs predominantly included GCB DLBCLs compared with CD21- type. The top classifier gene of CD21 expression was IGHM, and the five of nine Gene Ontology categories significant in CD21- DLBCLs included IGHM. Immunohistochemical analysis of 216 DLBCLs confirmed that overall survival of surface (s) IgM+ DLBCLs was significantly poorer than that of sIgM- DLBCLs (P = 0.013).