BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic condition causing widespread pain, fatigue, and sleep disturbances. Conventional treatments often provide limited relief, leading to growing interest in complementary therapies like ozone therapy. OBJECTIVE: This study aims to retrospectively evaluate the short- and medium-term efficacy of ozone therapy in patients with FMS, focusing on changes in pain, functional status, sleep quality, fatigue, anxiety, and depression. METHODS: Twenty-five FMS patients treated at the Physical Medicine and Rehabilitation outpatient clinic of University Hospital were included. Participants underwent a 10-session major ozone autohemotherapy protocol administered twice weekly. Key outcomes were measured using the Visual Analog Scale (VAS), Fibromyalgia Impact Questionnaire (FIQ), Hospital Anxiety and Depression Scale (HADS), Pittsburgh Sleep Quality Index (PSQI), and Fatigue Severity Scale (FSS) at baseline, post-treatment, and six months post-treatment. Generalized Estimating Equations were used for data analysis. RESULTS: VAS scores decreased from 6.4 to 3.68 post-treatment (p <
0.001) and partially increased to 4.12 at six months (p = 0.01). Similar trends were observed for FIQ, HADS, PSQI, and FSS. Tender points declined from 14.36 to 9.8 post-treatment (p <
0.001) and remained stable at 10.12 at six months (p = 0.289). FIQ scores improved from 59.2 to 39.08 post-treatment (p <
0.001) and stabilized at 40.12 at six months (p = 0.328). CONCLUSION: Ozone therapy demonstrates promising short- and medium-term efficacy in managing FMS symptoms, with significant improvements post-treatment. However, partial symptom recurrence at six months suggests the need for optimized protocols and further studies to ensure long-term sustainability.