Background: Fibromyalgia syndrome is a chronic multifaceted disease characterized by widespread pain, muscle stiffness, fatigue, unrefreshing sleep and cognitive disorders. To date, no medication has been shown to significantly improve pain, associated symptoms and Quality of Life in fibromyalgic patients. Methods: In this retrospective observational study, we analyzed data regarding 407 patients with diagnosis of fibromyalgia syndrome who between 2013 and 2016 have been prescribed orally ultramicronized palmitoylethanolamide tablets (Normast® Epitech Group SpA, Saccolongo, Italy) regardless of the concomitant pharmacological therapy (add-on treatment). Results: Regarding efficacy, in the 359 analyzed patients, the change over time in Visual Analogue Scale pain score was statistically significant, ranging from 75.84 (±15.15) to 52.49 (±16.73) (p<0.001). Regarding quality of life, the change over time in Fibromyalgia Impact Questionnaire score was statistically significant, ranging from 68.4 (±14.1) to 49.1 (±19.6) (p<0.001). In the treated population, only 36 patients (13,7%) reported Adverse Events predominantly of gastrointestinal type (diarrhea, dyspepsia, bloating, constipation, vomiting). Globally, 151 patients (57,63%) left the treatment due to inefficacy. Conclusion: The results of ultramicronized palmitoylethanolamide treatment in this retrospective analysis represent an important step for the development of a new and well-tolerated therapy for fibromyalgia syndrome, mostly suitable for these patients who need long-term treatments. Further methodologically stronger studies will be necessary to validate our observation.