Sonographic findings in 497 patients with suspected acute cholecystitis were analyzed prospectively. Combined use of primary and secondary sonographic signs led to excellent positive and negative predictive values. Positive predictive values for stones combined with either a positive sonographic Murphy sign (92.2%) or with gallbladder wall thickening (95.2%) were excellent for acute cholecystitis. Positive predictive value of these signs for patients requiring cholecystectomy was even higher (99.0%). Negative predictive values for combined use of primary and secondary signs to exclude acute cholecystitis were also excellent (95.0% for no stones and negative sonographic Murphy sign). Real-time sonography alone, using both primary and secondary signs, can be definitive in nearly 80% of patients with suspected acute cholecystitis. These patients require no further imaging evaluation. Sonography should be the screening test of choice in acute cholecystitis because it is cost effective, prospectively highly accurate, quick, and better at characterizing and detecting other abdominal lesions than cholescintigraphy. A proposed algorithm is described.