Background: Acute cholecystitis (AC) is a common differential for patients presenting to the emergency department (ED) with abdominal pain. The diagnostic accuracy of history, physical examination, and bedside laboratory tests for AC have not been quantitatively described., Objectives: We performed a systematic review to determine the utility of history and physical examination (H&P), laboratory studies, and ultrasonography (US) in diagnosing AC in the ED., Methods: We searched medical literature from January 1965 to March 2016 in PubMed, Embase, and SCOPUS using a strategy derived from the following formulation of our clinical question: patients-ED patients suspected of AC; interventions-H&P, laboratory studies, and US findings commonly used to diagnose AC; comparator-surgical pathology or definitive diagnostic radiologic study confirming AC; and outcome-the operating characteristics of the investigations in diagnosing AC were calculated. Sensitivity, specificity, and likelihood ratios (LRs) were calculated using Meta-DiSc with a random-effects model (95% CI). Study quality and risks for bias were assessed using the Quality Assessment Tool for Diagnostic Accuracy Studies., Results: Separate PubMed, Embase, and SCOPUS searches retrieved studies for H&P (n = 734), laboratory findings (n = 74), and US (n = 492). Three H&P studies met inclusion/exclusion criteria with AC prevalence of 7%-64%. Fever had sensitivity ranging from 31% to 62% and specificity from 37% to 74%; positive LR [LR+] was 0.71-1.24, and negative LR [LR-] was 0.76-1.49. Jaundice sensitivity ranged from 11% to 14%, and specificity from 86% to 99%; LR+ was 0.80-13.81, and LR- was 0.87-1.03. Murphy's sign sensitivity was 62% (range = 53%-71%), and specificity was 96% (range = 95%-97%); LR+ was 15.64 (range = 11.48-21.31), and LR- was 0.40 (range = 0.32-0.50). Right upper quadrant pain had sensitivity ranging from 56% to 93% and specificity of 0% to 96%; LR+ ranged from 0.92 to 14.02, and LR- from 0.46 to 7.86. One laboratory study met criteria with a 26% prevalence of AC. Elevated bilirubin had a sensitivity of 40% (range = 12%-74%) and specificity of 93% (range = 77%-99%); LR+ was 5.80 (range = 1.25-26.99), and LR- was 0.64 (range = 0.39-1.08). Five US studies with a prevalence of AC of between 10% and 46%. US sensitivity was 86% (range = 78%-94%) and specificity was 71% (range = 66%-76%); LR+ was 3.23 (range = 1.74-6.00), and LR- was 0.18 (range = 0.10-0.33)., Conclusion: Variable disease prevalence, coupled with limited sample sizes, increases the risk of selection bias. Individually, none of these investigations reliably rule out AC. Development of a clinical decision rule to include evaluation of H&P, laboratory data, and US are more likely to achieve a correct diagnosis of AC., (© 2016 by the Society for Academic Emergency Medicine.)