BACKGROUND: Altered mental status (AMS) is a very common emergency case, but the exact etiology of many AMS patients is unknown. Patients often manifest vague symptoms, thus, AMS diagnosis and treatment are highly challenging for emergency physicians. The aim of this study is to provide a framework for the assessment of AMS patients. This assessment should allow providers to better understand the etiology of mental status changes and therefore improve diagnostic skills and management. METHODS: This is a prospective cohort observational study. We recruited all adult patients with undifferentiated AMS at a single center tertiary care academic emergency department over 24 months (June 2009 to June 2011). Demographic characteristics, clinical manifestations, assessment approaches, causative factors, emergency treatments and outcomes were collected prospectively. RESULTS: In 1934 patients with AMS recruited, accounting for 0.93% of all emergency department (ED) patients, 1 026 (53.1%) were male, and 908 (46.9%) female. Their average age was 51.95±15.71 years. Etiologic factors were neurological (n=641; 35.0%), pharmacological and toxicological (n=421; 23.0%), systemic and organic (n=266; 14.5%), infectious (n=167; 9.1%), endocrine/metabolic (n=145; 7.9%), psychiatric (n=71; 3.9%), traumatic (n=38; 2.1%), and gynecologic and obstetric (n=35; 1.9%). Total mortality rate was 8.1% (n=156). The death rate was higher in elderly patients (≥60) than in younger patients (10.8% vs. 6.9%, P=0.003). CONCLUSIONS: Patients with AMS pose a challenge for ED physicians. The most frequently encountered diagnostic categories causing AMS were primary CNS disorders, intoxication, organ system dysfunction, and endocrine/metabolic diseases. AMS has a high fatality rate in the ED. AMS is an important warning signal for ED patients because of its potentially fatal and reversible effects. Prompt evaluation and treatment are essential to decreasing morbidity and mortality associated with AMS.