Background: The prognosis of refractory or relapsed(R/R) non-germinal center B cell (non-GCB) subtype diffuse large B cell lymphoma (DLBCL) is dismal without established standard salvage chemotherapy regimen. We designed a phase II trial to prospectively evaluate the efficacy and safety of the combination of lenalidomide and rituximab with the IMED (ifosfamide, methotrexate, etoposide and dexamethasone) regimen(L-R-IMED) in refractory or relapsed non-GCB DLBCL. Methods: Eligible participants were adults with non-GCB subtype, CD20 positive DLBCL who were refractory to or had relapsed after R-CHOP-based regimens. Patients received lenalidomide 10 mg orally per day on days 1 through 14 with R-IMED every 21 days for four to six cycles. The response was evaluated using PET-CT scan after every 2 cycles. The primary endpoint was objective response rate (ORR) and progression-free survival (PFS). Results: Between January 2014 and November 2017, 40 patients with non-GCB subtype, CD20 positive, R/R DLBCL were enrolled, and 40 were evaluable for response. The median age was 51 years (range 20–85 years) and 60% (24 of 40) were men and 40% (16 of 40) were women. 50% of the patient (n = 20) had refractory disease and 50% (n = 20) had relapsed disease. The ORR was 70% (28 of 40) with 55% (22 of 40) achieving a complete response. The median follow-up time was 14.8 months. The median PFS was 10.9 months (95% CI: 7.9-13.9 months) and the median PFS of patients had a complete response was 28.6 months (95%CI:8.6-48.5months). The median overall survival was not reached. The most common hematologic adverse event was neutropenia. The most common nonhematologic adverse event was fatigue. There was no treatment-associated death. None of our patients discontinued treatment due to significant hematological toxicities. Conclusions: Among patients with R/R non-GCB DLBCL, L-R-IMED showed promising efficacy and tolerability profile. The regimen needs to be further verified by phase III study.