Fibromyalgia syndrome (FMS) is characterized by diffuse musculoskeletal pain associated with daytime fatigue, sleep disturbance, cognitive deficits, and often further somatic symptoms. While some patients with FMS respond to standard treatment with amitriptyline, pregabalin, or duloxetine in combination with outpatient multimodal pain management, there are still many who do not benefit sufficiently from this treatment or suffer intolerable side effects. Effective treatment options are therefore needed to supplement conventional therapies. Naltrexone is used in many countries as an off-label therapy in low doses for several chronic immunomodulatory disorders, including FMS. However, the strength of evidence from previous randomized controlled trials is low. I report a patient with severe FMS who did not respond to conventional therapy. Instead, low-dose naltrexone (LDN) (4.5 milligrams per day) resulted in a significant and sustained improvement in most FMS symptoms. The results of this case report suggest that an off-label use of LDN in severe refractory FMS may be a viable option. However, the information base is currently limited, and studies are conflicting.