Background: Lymphoma patients (pts) with residual hypermetabolic lesions on PET imaging after salvage chemotherapy have extremely poor outcomes and may benefit from continued therapy after ASCT. Lenalidomide (len) has been used as maintenance in other hematologic malignancies, but its toxicity and efficacy are not well known in lymphoma pts following ASCT. Methods: We conducted a phase I trial of len maintenance after ASCT in lymphoma pts at high risk for relapse defined by residual PET positive lesions of SUV > 2.5 immediately prior to ASCT. Our primary objective was to determine the safety and dose-limiting toxicity (DLT) of len maintenance. A 3+3 de-escalation design was utilized with a starting dose of len at 10 mg on days 1 through 28 of each 28 day cycle (C). Len was initiated 28-100 days post-ASCT and planned for twenty four Cs. DLT was defined as non-hematologic toxicity ≥ grade (G)3 or hematologic toxicity ≥ G4 during the first 28 days of len. Enrollment began in 5/2012; reported data were collected through 1/2015. Results: Eight pts were enrolled and 6 pts are evaluable (4 diffuse large B-cell and 2 Hodgkin lymphomas). One pt withdrew consent and one progressed prior to initiation of len. Median age was 51 yrs (29-61), ECOG PS 0 (0- 1), prior therapies 3 (2-5). Median time on len was 7 Cs (2-24). Len was well tolerated and no DLT was observed at the 10 mg dose. Two pts required dose reduction to 5 mg due to treatment-related toxicities (after C7 and C3). Four pts had ≥ G2 non-hematologic adverse events possibly related to len including fatigue, bronchitis, and thrush. Three pts had transient ≥ G3 neutropenia. Two pts discontinued len (1 due to progression, 1 at investigator’s discretion). No secondary malignancies or study-related deaths were observed. Four of 6 pts remain on len and are progression free; 5 of 6 pts are alive with median follow-up of 195 days. Conclusions: We established safety of len after ASCT in pts with relapsed/refractory lymphomas and determined that len 10 mg daily is a well-tolerated maintenance dose in this setting. Preliminary clinical outcomes observed in this cohort of high-risk lymphoma pts are encouraging and will be validated in the ongoing phase II trial. Clinical trial information: NCT01575860