Relapsed/refractory mantle cell lymphoma (MCL) is difficult to treat. Rituximab (R) targets CD20 antigen on the surface of MCL cells while lenalidomide (Len) may target the microenvironment of MCL cells and enhance the antibody-dependent cellular cytotoxicity (ADCC) activity of R. To test this hypothesis, we initiated preclinical studies and a phase I/II clinical trial. In the preclinical study we found that Len and R induced growth inhibition and apoptosis of both cultured and fresh primary MCL cells. Len enhanced R-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Daily treatment with Len increased NK cells by 10 times in SCID mice. The combination of Len and R decreased tumor burden and prolonged survival of MCL-bearing SCID mice. In the phase I/II clinical trial, Eligible patients (pts) with MCL had 1–4 lines of prior therapies. Treatment consisted of Len given orally daily on days 1–21 of a 28-day cycle and R 375 mg/m 2 by IV infusion weekly for 4 weeks only during the first cycle with the first dose on Day 1 in Cycle 1. A standard 3+3 dose escalation was used to determine MTD with Len doses at 10 mg, 15 mg, 20 mg, and 25 mg. Detailed toxicity profile in phase I was reported previously (Wang et al, ASH 2007). Two DLT s occurred at 25 mg including 1 grade 3 hypercalcemia and 1 grade 4 non-neutropenic fever during the first cycle. Six patients from phase 1 were at 20 mg dosage level. One patient from phase 1 was initially at 25 mg dosage level and was subsequently reduced to 20 mg dosage level due to DLT. Eight patients have been enrolled in the phase II trial at MTD. In the 14 patients evaluated at 20 mg dosage level in phase II, median age was 68 (51–77); median prior therapies were 2 (1–4); median cycles received to date were 4 (range 2–26). Grade 3/4 hematologic toxic events included neutropenia (35), febrile neutropenia (2), and thrombocytopenia (11). There was no grade 3–4 anemia. Grade 3 non-hematologic toxic events included fatigue (2) and myalgia (1). Fourteen pts at MTD (20 mg) including 7 in phase I plus 7 in phase II were evaluable for response. Eight out of 14 pts achieved responses including 4 CRs, 4 PR s, 2 SD and 4 PD s. Conclusions: Lenalidomide in combination with rituximab provided a synergistically therapeutic effect on mantle cell lymphoma cells by enhancement of apoptosis and R-dependent NK cell-mediated cytotoxicity preclinically. Lenalidomide plus rituximab showed early evidence of response with a very favorable toxicity profile in a phase I/II clinical trial. Updated information will be presented at the conference.