OBJECTIVES: We sought to report the efficacy of oral melatonin as treatment for chronic tinnitus and to determine whether particular subsets of tinnitus patients have greater benefit from melatonin therapy than others. METHODS: This was a prospective, randomized, double-blind, crossover clinical trial in an ambulatory tertiary referral otology and neurotology practice. Adults with chronic tinnitus were randomized to 3 mg melatonin or placebo nightly for 30 days followed by a 1-month washout period. Each group then crossed into the opposite treatment arm for 30 days. The tests audiometric tinnitus matching (TM), Tinnitus Severity Index (TSI), Self Rated Tinnitus (SRT), Pittsburgh Sleep Quality Index (PSQI), and Beck Depression Inventory (BDI) were administered at the outset and every 30 days thereafter to assess the effects of each intervention. RESULTS: A total of 61 subjects completed the study. A significantly greater decrease in TM and SRT scores (p < 0.05) from baseline was observed after treatment with melatonin relative to the effect observed with placebo. Male gender, bilateral tinnitus, noise exposure, no prior tinnitus treatment, absence of depression and/or anxiety at baseline, and greater pretreatment TSI scores were associated with a positive response to melatonin. Absence of depression and/or anxiety at baseline, greater pretreatment TSI scores, and greater pretreatment SRT scores were found to be positively associated with greater likelihood of improvement in both tinnitus and sleep with use of melatonin (p<0.05). CONCLUSIONS: Melatonin is associated with a statistically significant decrease in tinnitus intensity and improved sleep quality in patients with chronic tinnitus. Melatonin is most effective in men, those without a history of depression, those who have not undergone prior tinnitus treatments, those with more severe and bilateral tinnitus, and those with a history of noise exposure.