BACKGROUND: Acute dyspnea and hypoxemia are 2 of the most common problems in the emergency room. Oxygen therapy is an essential supportive treatment to correct these issues. In this study, we investigated the physiologic effects of high-flow nasal oxygen cannula (HFNC) compared with conventional oxygen therapy (COT) in subjects with acute dyspnea and hypoxemia in the emergency room. METHODS: A prospective randomized comparative study was conducted in the emergency department of a university hospital. Forty subjects were randomized to receive HFNC or COT for 1 h. The primary outcome was level of dyspnea, and secondary outcomes included change in breathing frequency, subject comfort, adverse events, and rate of hospitalization. RESULTS: Common causes of acute dyspnea and hypoxemia were congestive heart failure, asthma exacerbation, COPD exacerbation, and pneumonia. HFNC significantly improved dyspnea (2.0 ؎ 1.8 vs 3.8 ؎ 2.3, P ؍ .01) and subject comfort (1.6 ؎ 1.7 vs 3.7 ؎ 2.4, P ؍ .01) compared with COT. No statistically significant difference in breathing frequency was found between the 2 groups at the end of the study. HFNC was well tolerated, and no serious adverse events were found. The rate of hospitalization in the HFNC group was lower than in the COT group, but there was no statistically significant difference (50% vs 65%, P ؍ .34). CONCLUSIONS: HFNC improved dyspnea and comfort in subjects presenting with acute dyspnea and hypoxemia in the emergency department. HFNC may benefit patients requiring oxygen therapy in the emergency room.