There is an unmet clinical need for elderly or unfit diffuse large B-cell lymphoma (DLBCL) patients ineligible for autologous stem cell transplantation. Lenalidomide is an immunomodulatory agent with antitumor activity in non-Hodgkin lymphoma, with an acceptable toxicity profile and manageable side effects. A 79-year-old Caucasian male with non-germinal center B-cell-like DLBCL achieved complete remission (CR) after first-line treatment with seven out of eight scheduled cycles of a polychemotherapy containing anthracycline, which had to be discontinued early due to the onset of atrial fibrillation. After 5 months, the patient had an early epicardial relapse. He underwent lenalidomide considering age, cardiological comorbidities, and chronic renal failure. After the third cycle, he achieved CR, confirmed at restaging after the sixth cycle of treatment. Lenalidomide was safe and well tolerated in a patient with atrial fibrillation developed after an anthracycline-based regimen and a relapse of the DLBCL. Moreover, this regimen was effective in a case with a rare extranodal involvement of the epicardium.