The ECOG-ACRIN E1412 study demonstrated a potential clinical benefit of adding lenalidomide to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) (R2CHOP) in newly diagnosed patients regardless of cell-of-origin (COO) and in patients with activated b-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL). Although the results are not practice changing, they support further studies of lenalidomide and/or novel lenalidomide analogues in frontline therapy of DLBCL.