Background Ultrasound is a focus oriented tool for differentiating among cardiopulmonary diseases. Its value in the hands of emergency physicians, with various ultrasound experience, remains uncertain. We tested the hypothesis that, in emergency department patients with signs of respiratory failure, a focused cardiopulmonary ultrasound along with standard clinical examination, performed by emergency physicians with various ultrasound experience would increase the proportion of patients with correct diagnoses at 4 hours after admission compared to standard clinical examination alone. Methods In this prospective multicenter superiority trial in Danish emergency departments we randomly assigned patients presenting with acute signs of respiratory failure to intervention or control in a 1:1 ratio by block randomization. Patients received a focused cardiopulmonary ultrasound examination within 4 hours from admission. Ultrasound results were unblinded for the treating emergency physician in the intervention group. Final diagnoses and treatment were determined by blinded review of the medical record after the patients´ discharge.Results From October 9, 2015 to April 5, 2017, we randomized 218 patients and included 211 in the final analyses. At 4 hours we found; no change in the proportion of patients with correct presumptive diagnoses; intervention 79·25% (95% CI 70·3-86·0), control 77·1% (95% CI 68·0-84·3), an increased proportion of correct treatment prescribed; intervention 79·3% (95% CI 70·3-86·0), control 65·7% (95% CI 56·0-74·3) and of patients who spent less than 1 day in hospital; intervention n=42 (39·6%; 25·8 38·4), control n=25 (23·8%; 16·5-33·0). No adverse events were reported. Conclusions Focused cardiopulmonary ultrasound added to standard clinical examination in patients with signs of respiratory failure had no impact on the diagnostic accuracy, but significantly increased the proportion of correct treatment prescribed and the proportion who spent less than 1 day in hospital.Trial registration https://clinicaltrials.gov/, number NCT 02550184.