The hyperimmunoglobulinemia D and periodic fever syndrome is proposed to be caused by a defect in the activity of mevalonate kinase enzyme which is involved in cholesterol and non-sterol isoprenoid biosynthesis. This autosomal recessive inherited auto-inflammatory syndrome is characterized by recurrent fever attacks, abdominal pain, lymphadenopathy, skin lesions and joint involvement. In this article, we present our therapeutic approach with the hypolipidemic agent, simvastatin, in a 12-year-old boy followed up with a diagnosis of hyperimmunoglobulinemia D and periodic fever syndrome. Simvastatin treatment of an adolescent with hyperimmunoglobulinemia D and periodic fever syndrome unresponsive to anti-inflammatory strategies has resulted in a favorable outcome. This treatment is thought to reduce the recurrent fever attacks by reducing the mevalonic acid increase or isopreniod shortage.