BACKGROUND Sedation and/or analgesia can relieve the patient-ventilator asynchrony. However, whether sedation and/or analgesia can benefit the clinical outcome of the patients with interface intolerance is still unclear. METHODS A retrospective study was performed on patients with interface intolerance who received noninvasive positive pressure ventilation (NIPPV) after extubation in seven intensive care units (ICU) of West China Hospital, Sichuan University. The primary outcome was rate of NIPPV failure (defined as need for reintubation and mechanical ventilation); Secondary outcomes were hospital mortality rate and length of ICU stay after extubation. RESULTS A total of 80 patients with oral-nasal mask (90%) and facial mask (10%) were included in the analysis. 41 out of 80 patients received sedation and/or analgesia treatment (17 used analgesia, 11 used sedation and 13 used both) at some time during NIPPV. They showed a decrease of NIPPV failure rate, (15% vs. 38%, P = 0.015; adjusted odd ratio [OR] 0.29, 95% confidence interval [CI] 0.10-0.86, P = 0.025), mortality rate (7% vs. 33%, P = 0.004; adjusted OR 0.14, 95% CI 0.03-0.60, P = 0.008), and the length of ICU stay after extubation. CONCLUSIONS This clinical study suggests that sedation and/or analgesia treatment can decrease the rate of NIPPV failure, hospital mortality rate and ICU LOS in patients with interface intolerance after extubution during NIPPV.