Background: Approximately 40% patients with an intermediate/high to high-risk IPI score will relapse in the first year after completion of standard therapy with R-CHOP. Lenalidomide, an immunomodulatory drug, has activity in relapsed diffuse large B-cell lymphoma (DLBCL). Our pre-clinical data demonstrated that lenalidomide enhances the natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity of rituximab in lymphoma cell lines, inhibits angiogenesis, and alters cytokine production. Methods: This is a phase II randomized study of lenalidomide versus lenalidomide and rituximab. The primary endpoint of the study is to assess the one-year relapse-free survival for patients treated with lenalidomide alone (Arm A) or the combination of lenalidomide and rituximab (Arm B). We expect that a 25% difference in relapse rates compared with current standard therapy will have clinical significance. With a sample size of 32 in each arm, we will have 80% power to detect a difference of 25% between the null hypothesis that the one-year relapse rate is 40% and the alternative hypothesis that the one-year relapse rate is 15% using a two-sided significance level of 2.5%. DLBCL patients with int/high or high-risk IPI score or patients with a positive PET scan mid-therapy will be eligible for the study. Patients on arm A will receive lenalidomide at a dose of 25 mg daily for 21 days of 28 days. Patients on arm B will receive lenalidomide at a dose of 20 mg daily for 21 days along with rituximab on day 8 of even-numbered cycles. Treatment on both arms will be continued for one year. Treatment will be discontinued for disease progression. Lenalidomide dose adjustments are incorporated in the protocol. Correlative studies include performing cytokine analysis at various time intervals (sIL-2R, IL-6, IL-15, IL-12, TNF-a, and IFN-g). Flow cytometric analysis will be performed to assess the change in the number of peripheral blood NK cells (CD4, CD8 and CD56). Genotyping analysis of potentially prognostic DNA polymorphisms (in FCGR3A) will be performed.Thus far, 20 patients of the planned 64 patients have been enrolled.