Background: We previously reported favorable safety and efficacy of lenalidomide plus rituximab in relapsed or refractory (R/R) mantle cell lymphoma (MCL) in a phase 1/2 trial (Wang et al, Lancet Oncol 2012). We performed an updated analysis of the phase 2 data after an extended follow up. We also investigated whether Ki-67 level affected response and survival in this study, as we recently reported that lower Ki-67 was associated with extremely high response rate to ibrutinib plus rituximab in R/R MCL (Wang et al, ASH 2014). Methods: Patients with R/R MCL were enrolled in this single arm phase 1/2 trial. In phase 2, lenalidomide was administered orally at 20 mg daily dose on days 1-21 of each 28-day cycle, and 375 mg/m² rituximab was administered intravenously weekly during the first cycle only. Treatment was continued until disease progression, stem-cell transplantation, or severe toxicity. The primary endpoint was overall response, and the secondary endpoint was survival. Analysis was by intention to treat. Results: 46 patients were enrolled, of which 42 were male. The median age was 66.5 (range 46-85). Median number of prior lines of therapy was 2 (range 1-4). At a median follow up of 24.7 months (range 1.2-96.1), 16 (34.8%) and 10 (21.7%) patients achieved CR and PR, respectively, with an ORR of 56.5%. An additional 10 (21.7%) patients achieved MR or SD. ORR was independent of age, gender, number of prior lines of therapy and Ki-67 at registration. Median time to response was 1.8 months (range 1.6-7.7). Median duration of response was 20.9 months (95% CI 10.9-NR). The median PFS was 14.1 months (95% CI 8.2-26.7), and median OS was 24.6 months (95% CI 16.8-33.7). The 12- and 24-month PFS rates were 53.1% and 39.9%, respectively. The 1-, 2- and 5-year OS rates were 82.6%, 52.2% and 26.1%, respectively. Lower Ki-67 at registration ( < 50%) and fewer prior lines of therapy ( < 2) were predictive of better PFS (HR = 0.242, 95% CI 0.070-0.715, P = 0.012; and HR = 0.245, 95% CI = 0.071-0.841, P = 0.025) and OS (HR = 0.267, 95% CI 0.110-0.648, P = 0.003; and HR = 0.363, 95% CI = 0.147-0.896, P = 0.028). Conclusions: Lenalidomide plus rituximab is efficacious in treating R/R MCL. Lower Ki-67 is associated with better survival outcomes. Clinical trial information: NCT00294632