In a recent phase II multicenter trial, 49 patients with relapsed or refractory aggressive NHL (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas) received oral lenalidomide monotherapy, 25 mg once daily on days 1 to 21, every 28 days, for 52 weeks, until disease progression or intolerance. The most common histology was diffuse large B-cell lymphoma. The median age was 65 years (range: 23 to 86). Patients had received a median of four prior treatment regimens; 56% were refractory to last therapy and 29% had received a prior ASCT. An objective response rate of 35% was observed in 49 treated patients, including a 12% rate of complete response/unconfirmed complete response. Responses were observed in each aggressive histologic subtype tested (19% ORR in patients with DLBCL). Of patients with stable disease or partial response at first assessment, 25% improved with continued treatment. Estimated median duration of response was 6.2 months, and median PFS was 4.0 months. The most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and thrombocytopenia (12.2%). The results of this study show that lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects.