A confirmatory international phase II trial (NHL-003) of single-agent lenalidomide was performed for patients with relapsed/refractory aggressive NHL that had received at least one prior treatment and had measurable disease. Patients received 25 mg oral lenalidomide once daily on days 1-21 of every 28-day cycle and continued therapy until disease progression or toxicity. 217 patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13% (29/217) CR, 22% (48/217) PR, and 21% (45/217) with stable disease. The ORR for DLBCL was 28% (30/108), 42% (24/57) for mantel-cell lymphoma, 42% (8/19) for grade 3 follicular lymphoma, and 45% (15/33) for peripheral T-cell lymphoma. Median progression-free survival for all 217 patients was 3.7 months [95% confidence interval (CI) 2.7-5.1]. For 77 responders, the median response duration lasted 10.6 months (95% CI 7.0-NR). Median response duration was not reached in 29 patients who achieved a CR and in responding patients with follicular lymphoma (FL)-III or mantle cell lymphoma (MCL). The most common adverse event was myelosuppression with grade 4 neutropenia and thrombocytopenia in 17% and 6%, respectively.The results of this international study confirm that lenalidomide is active in heavily pre-treated patients with relapsed or refractory DLBCL with manageable side effects.