Darier disease (DD) is an autosomal-dominant genodermatosis in which mutations in the ATP2A2 gene result in impaired intercellular adhesion and epidermal blistering. Treatment options usually rely on systemic retinoids, but a refractory disease is still a therapeutical challenge. Given the similarity of DD pathogenesis with Hailey-Hailey disease, concomitant treatment with low-dose-naltrexone (LDN) has been proposed. We present the case of a 34-year-old woman with a 20-year history of severe, biopsy-proven DD, previously treated with several unsuccessful topical and systemic treatments, including oral isotretinoin, cyclosporine, doxycycline, methotrexate, acitretin, and subcutaneous adalimumab. At presentation, she had widespread keratotic, crusted, brown papules on her trunk and proximal extremities. Treatment with oral LDN (4.5 mg/day in manipulated tablets) was then initiated while maintaining the current isotretinoin therapy. After three months, there was a nearly complete clearance of the lesions, and no adverse effects were reported.