Background: Lenalidomide (Len) was demonstrated to have significant single agent activity in relapsed aggressive B cell lymphoma (J Clin Oncol. 2008;26:4952-7). However, the safety and efficacy of Len in combination with standard immunochemotherapy is not known. Methods: A phase I/II study was designed to define the maximum tolerated dose and efficacy of Len administered on days 1-10 with standard R-CHOP chemotherapy (R2CHOP). Len dose escalation levels were 15 mg, 20 mg and 25 mg. All patients (pts) received 6 mg pegfilgrastim on day 2 and aspirin prophylaxis. Eligible pts were adults with newly diagnosed CD20 positive diffuse large B cell (DLBCL) or grade 3 follicular lymphoma (FL). Dose limiting toxicity (DLT) was defined as any grade 3 or higher non-hematological toxicity or a hematological toxicity resulting in a delay of the next cycle of chemotherapy. The response was evaluated using PET/CT by standard criteria (J Clin Oncol. 2007;25:579-586). Results: In the phase I portion, 3 pts received 15 mg, 3 received 20 mg and 6 received 25 mg of Len. No DLT was found and 25 mg was the recommended dose for phase II. 26 additional pts were enrolled on the 25 mg dose level in the phase II portion for a total of 32 pts at this level. The median age of these 32 pts was 64 years (19-87); 59% (19/32) were males. 28 pts (88%) had DLBCL and 4 (12%) pts had FL grade 3. International prognostic index (IPI) was low, low-intermediate, high-intermediate and high in 6, 13, 11 and 2 pts respectively. 8 pts (25%) experienced a grade 3 non-hematological toxicity and the most frequent were: febrile neutropenia (3 pts), fatigue (2 pts), thrombosis (2 pts), and dehydration (2 pts). Hematological toxicities were: grade 3 and 4 thrombocytopenia (16% and 25% of pts respectively); grade 3 and 4 neutropenia (13% and 75% of pts respectively). For 30 pts evaluable for response the overall and complete response rate was 100% and 83% respectively. Conclusions: Lenalidomide at a dose of 25 mg for days 1-10 is well tolerated when combined with standard R-CHOP21 chemotherapy. The overall and complete response rates are encouraging. Ultimately, a randomized trial will be needed to confirm the benefits of this novel combination.