INTRODUCTION: The prevalence of chronic otitis media with effusion (COME), and Eustachian tube dysfunction (ETD) is high in Down syndrome (DS) patients. This often necessitates multiple tympanostomy tube (TT) placements resulting in a higher rate of persistent tympanic membrane (TM) perforation requiring tympanoplasty for repair. OBJECTIVES: To assess risk factors for persistent perforation and outcomes of tympanoplasty in DS patients. METHODS: Retrospective case series of 91 ears in 69 DS patients with TM perforations, who were either observed or underwent tympanoplasty. Clinical features, surgical outcomes, and hearing outcomes were assessed. RESULTS: 91 ears were evaluated. Sixty perforations were observed, and 31 perforations were repaired. The closure rate was 54.8% for primary surgery, and 70.9% after secondary surgical interventions in the Tympanoplasty Group, compared to 33.0% spontaneous closure rate in the Observation Group (p < 0.001). The only risk factor for failed tympanoplasty repair was persistent COME/ETD (OR 27.2, p = 0.001). In the Observation Group perforations diagnosed at an older age, with >3 TT insertions, and with persistent COME/ETD were less likely to close spontaneously. Patients undergoing tympanoplasty had worse preoperative pure tone averages than those being observed, but significant improvement in air-bone gaps were noted in the Tympanoplasty Group (p = 0.02) post-operatively. Patients were often rehabilitated with hearing aids regardless of intervention (53.3% Observation Group, 48.4% Tympanoplasty Group). CONCLUSIONS: Persistent TM perforation in children with Down syndrome was associated with a history of COME/ETD, and multiple prior TT insertions. Tympanoplasty was successful for repair in most patients who underwent surgical intervention, but residual hearing loss was common.