We report the case of a 63-year-old man with a clearly established diagnosis of hairy cell leukemia, treated with multiple lines of chemotherapy, who complained of localized pain in the left humerus. Radiological findings showed a dystrophic-blastic area within the humeral head. Fine-needle biopsy confirmed the hypothesis of bone involvement of hairy cell leukemia. The patient underwent radiotherapy at a dose of 25 Gy, obtaining a complete clinical response with resolution of pain and a partial recovery of the normal radiological structure of the humerus after 2 months. In addition to the case report, we present a short review of the literature focusing on the role of radiotherapy in this subset of patients.