The histologic transformation (HT) of Waldenström macroglobulinemia (WM) into diffuse large-cell lymphoma is an uncommon but poor-prognostic event for which there is no standard therapy. Knowledge of this entity is mainly derived from largely retrospective studies, which report abysmal average survival rates even with the utilization of first-line chemoimmunotherapy and especially in patients who meet the high-risk criteria based on prognostic indices used for WM. We present the case of a 75-year-old man with high-risk, transformed WM who was ineligible for standard chemoimmunotherapy (due to pancytopenia and multiple comorbidities) and was consequently treated with tafasitabmab, an anti-CD19 monoclonal antibody plus lenalidomide. Tafasitamab plus lenalidomide (TAF/LEN) is a recently approved therapy for relapsed or refractory de novo diffuse large-cell lymphoma (DLCL) but has not been previously studied in transformed low-grade lymphomas or WM. We show that TAF/LEN resulted in a complete and durable response of the DLCL by PET/CT and a complete bone marrow response of lymphoplasmacytoid cells, including the normalization of complex cytogenetic abnormalities. The extraordinary response of our patient to TAF/LEN suggests that this combination may be an effective and tolerable therapy for transformed WM as well as relapsed or refractory non-transformed WM. Clinical trials of TAF/LN for the treatment of Waldenström macroglobulinemia are recommended.