Interleukin 21 (IL-21) and its receptor, IL-21R, play a key role in innate and adaptive immunity. In the present study, the effect of IL-21 and IL-21R on the pathogenesis of diffuse large B-cell lymphoma (DLBCL) was investigated. The serum levels of IL-21 were detected by enzyme-linked immunosorbent assay, and the expression of IL-21R on CD8+ T cells was examined through flow cytometry. The data showed that the serum level of IL-21 was significantly decreased in the patients with DLBCL compared with the healthy controls (P<0.001), whereas the expression of IL-21R was clearly elevated on the CD8+ T cells in the patients with DLBCL. Further analyses revealed that the downregulation of the IL-21 serum level was correlated with an increased tumor stage of DLBCL, while the expression of IL-21R on the CD8+ T cells was positively correlated with the tumor stage. Also, the serum level of IL-21 and the proportion of IL-21R on the CD8+ T cells were negatively correlated in the patients. Notably, it was identified that the proportion of IL-21R on the CD8+ T cells, but not the serum level of IL-21, was significantly upregulated in the patients with bone-marrow involvement and B symptoms. These results indicate that IL-21 and IL-21R may be involved in the pathogenesis of DLBCL, in which IL-21R may reflect the progression of the disease more accurately than the serum level of IL-21.