The purpose of this study was to compare ultrasound and CT in the diagnostic evaluation of right upper quadrant pain in adults in the emergency department. A retrospective review was conducted of adult emergency department encounters for right upper quadrant pain over a 5-year period, excluding those for prior cholecystectomy, current pregnancy, and trauma. Imaging study reports were reviewed for gallbladder and nongallbladder explanations of right upper quadrant pain and were considered positive for cholecystitis when two or more supportive features were present. Encounter outcomes were evaluated on the basis of pathology data and clinical management. Among the encounters, 2859 met the study inclusion criteria, and 18% met the study definition of cholecystitis by pathologic or clinical criteria. The following metrics showed no statistically significant difference between ultrasound and CT, respectively: sensitivity, 61% and 55%; specificity 91% and 92%; positive predictive value, 63% and 63%; and negative predictive value, 91% and 90%. Both modalities were performed in 20% of encounters. In the subgroup analysis, ultrasound showed an acute nongallbladder abnormality that was missed at a preceding CT examination in only 1 of 238 cases (0.4%). CT showed an acute nongallbladder abnormality missed at a preceding ultrasound examination in 103 of 322 cases (32%). CT is noninferior to ultrasound in both ruling in and ruling out the diagnosis of cholecystitis in adult patients undergoing emergency evaluation of right upper quadrant pain and offers the advantage of depicting acute nongallbladder abnormalities.