Melorheostosis and osteopoikilosis are rare sclerosing bone dysplasias that can occasionally coexist and present with significant musculoskeletal and neurologic symptoms. This case report describes a 27-year-old man with an 8-year history of chronic right gluteal and posterior thigh pain, exacerbated by sitting and refractory to conservative management. Imaging demonstrated extensive melorheostosis and osteopoikilosis involving the right lower limb, along with two soft-tissue masses in the gluteal region causing compression of the sciatic nerve.

Given the severity of symptoms and radiologic evidence of nerve compression, the patient underwent surgical excision of the masses through a dual surgical approach to achieve sciatic nerve decompression. Intraoperatively, the lesions were successfully removed without complications. Postoperatively, the patient experienced complete resolution of pain and regained normal tolerance for sitting and sleeping, with sustained symptom relief over a 15-month follow-up period.

This case highlights an uncommon but clinically significant presentation of combined melorheostosis and osteopoikilosis leading to peripheral nerve compression. Although these conditions are typically benign and often incidentally discovered, they may occasionally form expansile or mass-like lesions that produce significant morbidity. Surgical intervention should be considered when symptomatic lesions cause neurovascular compression, as decompression can result in excellent and durable functional outcomes.