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To retrospectively study the effects of minimally invasive single-stage multilevel surgery (MISS MLS) for treating patients with obstructive sleep apnea/hypopnea syndrome (OSA) on quality of life (QOL).All OSA patients with multilevel obstruction who failed or refused continuous positive airway pressure (CPAP) treatment and then underwent Pillar implants and temperature-controlled radiofrequency of the base of tongue (RFBOT) were enrolled. The subjective symptoms and QOL (SF-36 Taiwan Standard Version 1.0) parameters were collected preoperatively and a minimum of 3 months postoperatively. Postoperative morbidity and complications were also recorded.Thirty-seven patients (30 men, 7 women; mean age = 46.8 years; mean BMI = 23.9 kg/m2) were enrolled. The mean Epworth Sleepiness Scale changed from 12 ± 4.3 to 10.6 ± 4.3 (P = .004, Wilcoxon signed-rank test). The mean snoring visual analog scale reduced from 9.5 ± 1.3 to 4.0 ± 2.0 (P < .0001). The mean score of SF-36 increased from 65.5 ± 19.6 to 75.2 ± 16.7 (P = .001). The SF-36 subscales showed statistically significant changes, especially in bodily pain, role-emotional, and general health.The study demonstrated that MISS MLS was effective on QOL in selected patients for treating OSA patients who are unresponsive to conservative OSA therapy.