Surgical interventions, like barbed reposition pharyngoplasty (BRP), are a valuable alternative for patients with obstructive sleep apnea (OSA) who are unable to tolerate continuous positive airway pressure (CPAP). However, predicting surgical success remains challenging, partly due to the contribution of non-anatomical factors. Therefore, combined medical treatment with acetazolamide, known to stabilize respiratory drive, may lead to superior surgical results. This double-blind, parallel-group randomized controlled trial evaluates the efficacy of acetazolamide as an add-on therapy to BRP in OSA. A total of 26 patients with moderate to severe OSA undergoing BRP were randomized to receive either acetazolamide or placebo post-surgery for 16 weeks. The group who was treated with BRP in combination with acetazolamide showed a reduction in AHI of 69.4%, significantly surpassing the 32.7% reduction of the BRP + placebo group (p p p = 0.28). Based on these results, acetazolamide as an add-on therapy following BRP surgery shows promise in improving outcomes for OSA patients, addressing both anatomical and non-anatomical factors.