Emphysematous cholecystitis is a rare variant of acute cholecystitis, most frequently seen in elderly, debilitated, or diabetic patients. This report documents the development of fulminant sepsis due to acalculous cholecystitis after endoscopic retrograde cholangiopancreatogram (ERCP) in an otherwise healthy patient with suspected malignant obstructive jaundice. Three other cases of acute cholecystitis have been reported in the literature after ERCP. Although not proven to prevent infectious complications during ERCP, strong consideration should be given to prophylactic antibiotics in patients with suspected malignant obstruction and/or coexistent medical illness, eg, diabetes. When attempts at decompression of the obstructed biliary system by endoscopy fail, decompression by percutaneous or surgical routes should be considered in a timely fashion.