Identifying features that differentiate patients with H1N1 influenza infection from those with other conditions may assist clinical decision making during waves of pandemic influenza activity. From April 27 to June 15, 2009, nasopharyngeal swabs were obtained from all adults presenting to two urban emergency departments (EDs) with illness including fever or respiratory symptoms. H1N1 infection was detected by reverse transcriptase-polymerase chain reaction. Chart review was performed to compare cases of H1N1 influenza (n = 117) to matched controls. The median age of cases was 35 years versus 50 years for controls (p < .001). In those with pre-existing conditions, asthma was present in 31% of cases versus 14% of controls (OR 2.6, 95% CI 1.3-5.4). Cough (OR 7.8, 95% CI 3.2-19), fever (OR 3.0, 95% CI 1.7-5.4), headache (OR 2.0, 95% CI 1.2-3.2), and myalgias (OR 1.9, 95% CI 1.2-3.1) were significantly more common in H1N1 cases. The median white blood cell count was 5.7 × 109/mL versus 10.9 × 109/mL (p < .001). The combination of fever and cough had an OR of 5.3. Fever, cough, low white blood cell (WBC) count, and tachycardia had the highest OR at 11. The absence of both fever and cough had a negative predictive value of 99%, but this occurred in only 8% of controls. In patients presenting to the ED, the combination of fever, cough, tachycardia, and WBC count < 10 × 109/mL was suggestive of H1N1 influenza infection. However, clinical features could not reliably distinguish influenza from other acute respiratory illnesses in adult ED patients.