Background: A fast and diagnostic accurate tool to assess the unselected category of high-acuity patients, in whom the underlying pathology is not always obvious, is needed in the emergency departments (ED). We aim to describe the feasibility, validity and diagnostic yield of a routine whole-body-focused ultrasonography (wbf-us) in an unselected group of high-acuity ED patients. Methods: In a prospective observational study, a convenience sample of ED patients (≥ 18 years) with a high-acuity score or systolic blood pressure < 100 mmHg received a routine wbf-us of the heart, lungs, abdomen and deep veins by two non-expert sonographers. Final diagnosis was established by experienced auditors. Investigators were blinded to the patients’ medical history and emergency physicians and auditors were blinded to the investigators assessments. Diagnostic accuracy was assessed by comparing the investigators’ ultrasonography findings to a structured double-blinded clinical audit of patient files. Results: We included 171 patients, initiated a whole-body-focused ultrasonography examination (wbf-us) in 160 and completed it in 128 patients with an average time of a full examination of 28 min. We found pathology in 65/171 (38%) of the patients whose most frequent symptoms upon arrival were cardiopulmonary. Among the patients who received wbf-us, we found the majority of pathology by wbf-us of the lungs (n = 50, 31%), the heart (n = 26, 16%), few in the abdomen (n = 5, 3%) and none in the deep veins. The overall sensitivity was 50–100%, specificity 84–94%, positive predictive value 11–44% and negative predictive value 94–100%. Conclusion: Focused cardiopulmonary ultrasonography might be considered for routine use in high-acuity ED patients with cardiopulmonary symptoms whereas focused ultrasonography of the abdomen and deep veins performed by non-expert sonographers only seems indicated in selected patients. Trial registration Danish Data Protection Agency (ID 13/12076). Committee on Biomedical Research Ethics for the Region of Southern Denmark (ID S-20130047).