Children with down syndrome (DS) are more liable to develop obstructive sleep apnea (OSA) which is usually treated with adenotonsillectomy. However, OSA may persist in many of those patients after the procedure. The aim of this study was to assess the efficacy of drug-induced sleep endoscopy (DISE)-directed treatment in management of DS children with persistent OSA after adenotonsillectomy. Sixteen DS children with persistent OSA after adenotonsillectomy were evaluated. DISE was done in the operating theatre to identify the site of obstruction, and surgical intervention was performed according to the finding. Polysomnographic study was used pre-and post-operatively to measure the outcome. DISE revealed obstruction in different sites of the airway. DISE-directed treatment was done according to the site of obstruction. Polysomnographic study showed postoperative significant changes for all parameters. The authors achieved improvement of overall apneahypopnea index which was normalized in seven patients (44%). In conclusion, DISE-directed treatment is an effective procedure for persistent OSA in DS children who underwent adenotonsillectomy. However, residual obstruction in those children may be due to many characteristic features that cause narrowing of the airway.