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The purpose of the study was to determine whether pleural effusion (PE) is associated with a failure of high-flow nasal cannula (HFNC) therapy.We conducted a single-center retrospective study. Seventy-three patients with acute respiratory failure given HFNC therapy between January 2012 and December 2014 were reviewed. HFNC failure was defined as intubation or noninvasive positive pressure ventilation following HFNC therapy. The numbers of quadrants with consolidation or ground glass opacity were counted on chest radiographs performed within 24 hours before starting HFNC therapy, and the PE score was calculated. PE score was the original score, verified by the computed tomographic images of some of the study patients.Overall, 29 of 73 experienced HFNC failure. PE score was significantly greater in the HFNC failure group, but the number of quadrants with opacity was not significantly different. Age and Sequential Organ Failure Assessment (SOFA) score were significantly greater in the HFNC failure group. The PE (odds ratio, 1.49; 95% confidence interval, 1.10-2.02; P = .01) and SOFA (odds ratio, 1.33; 95% confidence interval, 1.05-1.68; P = .02) scores were independently associated with HFNC failure in multivariate analysis.The extent of PE on chest radiograph and SOFA score were associated with HFNC failure.