To determine the clinical significance of CD5 expression in diffuse large B-cell lymphoma (DLBL) without a clinical history of low-grade B-cell lymphoma, we have reviewed the clinical features and therapeutic outcome of 25 patients with de novo CD5-positive DLBL, and compared the results with those of 87 patients with CD5-negative DLBL and 22 patients with mantle cell lymphoma (MCL). The patients with de novo CD5-positive DLBL had clinical characteristics of elderly onset (median age 63, range 37-91), and female predominance (male/female 10/15). 21 (84%) of these patients had extranodal involvement at presentation, with great variation in the sites. In comparison with the patients with CD5-negative DLBL, the treatment outcome for the patients with de novo CD5-positive DLBL was very poor with frequent relapse. The failure-free survival curve was almost identical to that of patients with MCL, showing that standard chemotherapy for DLBL was not effective for most of the patients with de novo CD5-positive DLBL. These findings suggest that de novo CD5-positive DLBL forms a distinct subgroup of DLBL.