Fibromyalgia is a chronic disorder with a very complex symptomatology. Although generalized severe pain is considered to be the cardinal symptom of the disease, many other associated symptoms, especially non-restorative sleep, chronic fatigue, anxiety, and depressive symptoms also play a relevant role in the degree of disability characteristic of the disease. Ozone therapy, which is used to treat a wide range of diseases and seems to be particularly useful in the treatment of many chronic diseases, is thought to act by exerting a mild, transient, and controlled oxidative stress that promotes an up-regulation of the antioxidant system and a modulation of the immune system. According to these mechanisms of action, it was hypothesized that ozone therapy could be useful in fibromyalgia management, where the employed therapies are very often ineffective.Sixty-five patients with fibromyalgia, according to the definition of the American College of Rheumatology (Arthritis Rheum 1990; 33: 160-172), were treated at the MEDE Clinic (Sacile, Pordenone, Italy) from February 2016 to October 2018. Females were 55 and males were 10; age ranged from 30 to 72 years, and the time from fibromyalgia diagnosis ranged from 0.5 to 33 years. Treatment was made by autohemotransfusion in 55 patients and by ozone rectal insufflations in 10 patients, according to SIOOT (Scientific Society of Oxygen Ozone Therapy) protocols, twice a week for one month and then twice a month as maintenance therapy.We found a significative improvement (>50% of symptoms) in 45 patients (70%). No patient reported important side effects. In conclusion, at our knowledge, this is the largest study of patients with fibromyalgia treated with ozone therapy reported in the literature and it demonstrates that the ozone therapy is an effective treatment for fibromyalgia patients without significant side effects.At the moment, ozone therapy seems a treatment that, also because without any side effect, is possible to be proposed to patients with fibromyalgia that are not obtaining adequate results from other available treatments and it can be considered as complementary/integrative medicine.