BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is a type of aggressive lymphoid malignancy, which can present with an array of clinical features. DLBCL is notorious for having the highest rate of mortality in the developed areas of the world among the non-Hodgkin lymphomas (NHL). Although lymph node involvement is most commonly encountered, extranodal occurrence is also seen in up to 30% of the cases with involvement of structures such as the skin, lung, gastrointestinal tract, and musculoskeletal tissues. In view of the high mortality, especially in patients with delayed diagnoses, recognizing symptoms of this disease is vital for timely diagnosis and successful treatment. CASE REPORT We present the case of a 31-year-old white man with isolated shoulder pain. After the most common causes of shoulder pain were investigated and ruled out, further evaluation with an X-Ray, magnetic resonance imaging (MRI) scan, and biopsy revealed that B-cell lymphoma was the unlikely source of the pain. The patient received appropriate chemotherapy and achieved remission, as confirmed by a positron emission tomography scan. CONCLUSIONS This case highlights the uncommon clinical presentation of DLBCL with isolated shoulder pain. With primary bone DLBCL accounting for less than 2% of bone malignancies involving structures such as the femur, humerus, vertebra, and pelvis, this case reiterates the importance of further investigations and the possibility that bone pain may be the only clinical presentation of an underlying lymphoma. Examination by X-ray, MRI, and bone biopsy should be done to confirm diagnosis, followed by treatment with combined chemotherapy and immunotherapy.