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Diffusely increased uptake is more commonly observed than focal uptake in the spleen on a whole-body [18F] fluorodeoxyglucose-positron emission tomography/computed tomography. The significance of diffusely increased splenic uptake varies in different clinical settings. On a pre-therapeutic scan for lymphoma, splenic uptake, greater than hepatic uptake, is a relative reliable indication of lymphomatous involvement of the spleen, unless the patient has a history of recent cytokine administration. In HIV infection, increased splenic uptake is usually noted in the early stage of the disease, which could reflect massive stimulation of B-cells in the spleen by nonreplicating antigenic material. Diffusely increased splenic uptake may also be present in sarcoidosis, malaria, and many inflammatory or hematopoietic diseases. Therapeutic-related reactive splenic uptake concurrent with bone marrow uptake is often secondary to administration of granulocyte colony-stimulating factor for myelosuppression or high-dose interferon-α-2b adjuvant therapy for melanoma.