OBJECTIVE To assess the feasibility of remifentanil-based sedation in hypoxemic acute respiratory failure (HARF) patients refusing to continue noninvasive ventilation (NPPV) for intolerance to two different interfaces-helmet and total face mask. METHODS Prospective uncontrolled clinical investigation in a 14-bed ICU of an university hospital in Italy. METHODS Thirty-six patients with persistent severe HARF who complained of discomfort and asked for interruption of NPPV session. METHODS Patients started sedation with remifentanil (0.025 μg kg(-1) min(-1)) and the infusion rate was increased by 0.01 μg kg(-1) min(-1) every minute to a maximum of 0.12 μg kg(-1) min(-1) to obtain patient comfort. RESULTS Twenty-two out of 36 patients (61%) with median (IQR) SAPS II score of 32 (30, 38) continued the NPPV treatment after the introduction of remifentanil infusion. In this success group, median (IQR) respiratory rate decreased from 34 (31, 37) to 24 (20, 26) min(-1) (p < 0.0001) and PaO(2)/FiO(2) ratio increased from 156 (144, 176) to 270 (210, 300) mmHg (p < 0.0001) after 1 h of NPPV with remifentanil-analgosedation either with helmet or total face mask. Fourteen patients failed to continue the noninvasive treatment and were intubated after a mean of 2.5 ± 2.3 h; they showed a respiratory rate decrease from 35 (30, 38) to 27 (25, 35) min(-1) (p = 0.02) and an inability to increase the PaO(2)/FiO(2) ratio above 180 mmHg. The ICU mortality in the failure group patients was 50 versus 14% in the NPPV success group (p < 0.05). The mean remifentanil dose administered was 0.07 ± 0.03 μg kg(-1) min(-1). CONCLUSIONS This clinical study suggests that a remifentanil-based sedation protocol can decrease the rate of failure in patients with intolerance to NPPV.