CD5-positive (CD5(+)) diffuse large B-cell lymphoma (DLBCL) has a poor prognosis and high incidence of central nervous system (CNS) relapse, even in the rituximab era. To determine the gene expression profile of CD5(+) DLBCL, total RNA from 90 patients with DLBCL, including 33 CD5(+) DLBCL and 57 CD5-negative (CD5(-)) DLBCL patients, was examined using Agilent human oligo microarrays. These cases were separated into 78 activated B-cell-like (ABC) DLBCLs and 12 germinal center B-cell-like (GCB) DLBCLs. All cases of CD5(+) DLBCL were classified as ABC DLBCLs. The classifier based on gene expression used in a supervised analysis correctly identified CD5 expression in the DLBCL and ABC DLBCL samples. The gene most relevant to CD5 expression was SH3BP5. Enriched GO categories in the CD5(+) ABC DLBCL signature gene set included multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. The present study, which includes the largest reported number of patients with CD5(+) DLBCL, confirmed that most CD5(+) DLBCLs are ABC DLBCLs, suggesting that therapeutic strategies for ABC DLBCL may be effective for the treatment of CD5(+) DLBCL. Our CD5(+) ABC DLBCL signature gene set may provide insights into the cause of the high frequency of CNS relapse in CD5(+) DLBCL.