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Challenges of assessing response to therapy in non-Hodgkin's lymphoma of the bone. A 17-year-old male adolescent was diagnosed with diffuse large B cell lymphoma arising from the right humeral head. The lymphoma was found to be isolated to the bone, with a very small extraosseous component. After completion of a standard chemotherapy regimen, the Positron Emission Tomography-Computed Tomography (PET-CT) became PET negative but the CT and MRI appeared mostly unchanged in appearance, suggesting refractory disease. Repeat biopsy confirmed that no lymphoma remained, and he was in complete remission. Three months after completion of therapy, MRI continued to be abnormal. This case illustrates the unique challenges posed by the imaging characteristics of bone lymphoma, both during and after therapy. Biopsy is definitive but causes additional morbidity and may not be necessary. Imaging is done routinely to assess response to therapy, as with this patient, but in lymphomas of the bone imaging can be misleading and can lead to unnecessary procedures or follow-up imaging.