Sclerosing mesenteritis is a rare, idiopathic, and benign mesenteric lesion that is characterized by fat necrosis, fibrosis, and chronic inflammation. We report a case of sclerosing mesenteritis presenting as recurrent abdominal pain in an HIV-positive patient. Because of the wider differential diagnosis in such cases, the patient underwent an extensive workup culminating in a laparoscopy with biopsy. Tamoxifen has been shown to be useful in the treatment of desmoid tumors and idiopathic retroperitoneal fibrosis. We present the first case of sclerosing mesenteritis to respond to tamoxifen therapy. Because this drug is relatively safe and simple to dose, its utility as therapy for patients with this benign but debilitating disease should be considered.