Summary Background When used with standard diagnostic testing, point-of-care ultrasonography might improve the proportion of patients admitted with respiratory symptoms who are correctly diagnosed 4 h after admission to the emergency department. We therefore assessed point-of-care ultrasonography of the heart, lungs, and deep veins in addition to the usual initial diagnostic testing in this patient population. Methods In a prospective, parallel-group trial in the emergency department at Odense University Hospital, Odense, Denmark, patients (≥18 years) with a respiratory rate of more than 20 per min, oxygen saturation of less than 95%, oxygen therapy, dyspnoea, cough, or chest pain were randomly assigned in a 1:1 ratio with a computer-generated list to a standard diagnostic strategy (control group) or to standard diagnostic tests supplemented with point-of-care ultrasonography of the heart, lungs, and deep veins (point-of-care ultrasonography group). The primary endpoint was the percentage of patients with a correct presumptive diagnosis 4 h after admission to the emergency department. Only the physicians doing the primary clinical assessment and the auditors were masked. Analyses were by intention to treat. The study is registered with ClinicalTrials.gov, number NCT01486394. Findings Between Dec 7, 2011, and March 15, 2013, 320 patients were randomly assigned to the control group (n=160) and point-of-care ultrasonography group (n=160). 158 patients in the point-of-care ultrasonography group and 157 in the control group were analysed. 4 h after admission to the emergency department, 139 patients (88·0%; 95% CI 82·8–93·1) in the point-of-care ultrasonography group versus 100 (63·7%; 56·1–71·3) in the control group had correct presumptive diagnoses (p<0·0001). The absolute and relative effects were 24·3% (95% CI 15·0–33·1) and 1·38 (1·01–1·31), respectively. No adverse events were reported. Interpretation Point-of-care ultrasonography is a feasible, radiation free, diagnostic test, which alongside standard diagnostic tests is superior to standard diagnostic tests alone for establishing a correct diagnosis within 4 h. It should therefore be considered for routine use as part of the standard diagnostic tests in the emergency department for patients admitted with respiratory symptoms. Funding University of Southern Denmark, Odense University Hospital, and Højbjerg Fund.