Rationale: A low respiratory arousal threshold is a physiological trait involved in obstructive sleep apnea(OSA) pathogenesis. Trazodone may increase arousal threshold without compromising upper airway muscles, which should improve OSA. Objectives: We aimed to examine how trazodone alters OSA severity and arousal threshold. We hypothesized that trazodone would increase the arousal threshold and improve the apnea/hypopnea index (AHI) in selected OSA patients. Methods: Subjects were studied on 2 separate nights in a randomized cross-over design. 15 unselected OSA subjects (AHI≥10/h) underwent a standard PSG plus an epiglottic catheter to measure the arousal threshold. Subjects were studied after receiving trazodone (100mg) and placebo with 1-week between conditions. The arousal threshold was calculated as the nadir pressure prior to electrocortical arousal from approximately 20 spontaneous respiratory events selected randomly. Measurements and Main Results: Compared to placebo, trazodone resulted in a significant reduction the AHI (38.7 vs. 28.5 events/hr, P=0.041), without worsening oxygen saturation or respiratory event duration. Trazodone was not associated with a significant change in the NREM arousal threshold (-20.3 vs. -19.3 cmH2O, P=0.51) compared to placebo. In subgroup analysis, responders to trazodone spent less time in N1 sleep (20.1% placebo vs. 9.0% trazodone, P=0.052) and had an accompanying reduction in arousal index, whereas non-responders were not observed to have a change in sleep parameters. Conclusions: These findings suggest that trazodone could be effective therapy for OSA patients without worsening hypoxemia. Future studies should focus on underlying mechanisms and combination therapies to eliminate OSA. Clinical Trial Registration#: NCT01817907.