Purpose: There are limited data available about the role of sedation and analgesia during noninvasive positive pressure ventilation (NPPV). The objective of study was to estimate the effect of analgesic or sedative drugs on the failure of NPPV. Methods: We studied patients who received at least 2 h of NPPV as first-line therapy in a prospective observational study carried out in 322 intensive care units from 30 countries. A marginal structural model (MSM) was used to analyze the association between the use of analgesic or sedative drugs and NPPV failure (defined as need for invasive mechanical ventilation). Results: 842 patients were included in the analysis. Of these, 165 patients (19.6 ) received analgesic or sedative drugs at some time during NPPV; 33 of them received both. In the adjusted analysis, the use of analgesics (odds ratio 1.8, 95 confidence interval 0.6?5.4) or sedatives (odds ratio 2.8, 95 CI 0.85?9.4) alone was not associated with NPPV failure, but their combined use was associated with failure (odds ratio 5.7, 95 CI 1.8?18.4). Conclusions: Slightly less than 20 of patients received analgesic or sedative drugs during NPPV, with no apparent effect on outcome when used alone. However, the simultaneous use of analgesics and sedatives may be associated with failure of NPPV.