Background: Outcomes remain poor for patients with relapsed refractory DLBCL and HGBCL, especially those ineligible for a stem cell transplant or CAR T-cell therapy. Lenalidomide has efficacy in these groups, most notably in the activated B-cell like (ABC) subtype when defined by gene expression profiling. We analyzed the outcomes of consecutive patients with DLBCL treated with lenalidomide, focusing on characteristics such as transformed histology and MYC translocation status. Methods: We performed a retrospective review of consecutive patients with transformed indolent NHL, DLBCL, and HGBCL treated with lenalidomide at the University of Rochester between 2011-2018. Cell of origin was determined by Hans algorithm and FISH was performed to detect MYC, BCL2, and BCL6 translocations. Kaplan Meier estimates and descriptive statistics were utilized for analysis. Results: 62 patients were identified with a median age of 76 years, the majority with > 2 prior therapies. ORR was 43.5%, including 14 patients with a CR. Median PFS was 4.6 months with 18 patients achieving a PFS > 1 year. Median OS was 14 months. No difference in PFS, OS, or ORR was observed between the de novo germinal center b-cell (GCB) and non-GCB populations (PFS 4 vs. 5 months, p = 0.87). 16 patients with transformed FL had a median PFS of 24 months and a median OS of 46.7 months (vs. de novo GCB OS of 7.8 months, p = 0.02). Notably, 6/7 MYC+ patients achieved an objective response, including 3 with a CR. All patients with double and triple hit disease had an objective response, including two PRs and one CR. Conclusions: Our experience confirms the clinical activity of lenalidomide in heavily pretreated older adults with DLBCL. Outcomes did not differ by cell of origin using the Hans immunohistochemistry algorithm and durable responses were observed, particularly in transformed FL. Nearly all of the MYC+ patients responded, including those with double/triple hit genetics, and almost half achieved a CR. Based on our data, lenalidomide may be an optimal bridge to consolidative cellular therapy in high-risk patients irrespective of genotype, particularly in transformed indolent histologies.