Resveratrol is a polyphenolic compound with well-documented anti-tumor properties. Despite reports of its efficacy in chronic B lymphocytic leukemia, little is known regarding the antiproliferative and/or proapoptotic effects of resveratrol in other B-cell malignancies. Diffuse large B cell lymphoma (DLBCL) has recently been subdivided into three major categories or subtypes, each with apparently distinct etiologies, gene expression profiles, and responses to conventional chemotherapy. These three DLBCLs comprise germinal center B cell (GC), activated B cell (ABC), and primary mediastinal DLBCL. Herein, we report that treatment of the OCI-LY18 B-cell lymphoma with resveratrol induced cell cycle arrest and apoptosis in a dose-dependant manner. Preliminary analyses suggest that OCI-LY18 exhibits a surface immunophenotype indicative of a GC DLBCL. The molecular mechanisms underlying cell cycle arrest by resveratrol were also investigated. We report herein that resveratrol induced the expression of p27 concomitant with inhibition of cdk2 and a decreased phosphorylation of the retinoblastoma protein (pRb). Resveratrol also induced the up-regulation of p53. In addition, resveratrol treatment resulted in the phosphorylation of p53 on Ser15/37, modifications that corresponded to the upregulation of p53. These data suggest that resveratrol induces growth arrest in OCI-LY18 via a mechanism that involves upregulation of p27 and p53. These results suggest that resveratrol might be beneficial as a novel treatment of GC DLBCL.