Aim: Tinnitus is the perception of sound in the absence of an apparent acoustic stimulus. A widespread and highly debilitating disease difficult to cure. Several treatments have been advocated for tinnitus in the last years, including surgery, pharmacotherapy, counseling, cognitive behavioral therapy, sound therapy, but unfortunately without definitive conclusions. The surgery treatments could represent an important therapeutic choice on specific subgroups of tinnitus with defined causes but obviously this approach represent an invasive treatment and it should be considered with extreme caution and then, alternative pharmacological options should be investigated., Methods: In this retrospective study 30 patients with tinnitus were treated with sulodexide (250 LSU BID, in the morning and in the evening) and melatonin (3 mg in the evening before going to sleep) for 80 days. The evaluations were performed comparing different parameters at basal (T0) and after 40 days (T1) and 80 days (T2) of treatment., Results: The results of Tinnitus Handicap Inventory (THI) and acufenometry showed a significative improvement of tinnitus after treatment with sulodexide and melatonin. In particular, THI total score was reduced from 37±20 to 27±18 (P<0.001) and 21±19 (P<0.001) at T1 and T2, respectively. The percentage of patients with improved symptoms (i.e. reduced score at THI) was 76.7% at T1 and 90.0% at T2. Finally a significant improvement was also detected in the tone audiometry test. No side effects were observed during the treatment period., Conclusion: In conclusion, the combined use of sulodexide, a natural glycosaminoglycan with antithrombotic, profibrinolytic and vascular anti-inflammatory properties used in the treatment of many vascular diseases, included the vertigo of vascular origin and melatonin, a neurohormone produced by the pineal gland and related to multiple physiological functions, confirms to an important and promising therapeutically option in the tinnitus management.