Abstract Acute acalculous cholecystitis (AAC) is an insidious and increasingly recognized complication of critical illness, whose pathogenesis is poorly understood and clinical picture obscure. Diagnosis is difficult and there is no consensus on treatment. The medical records of all ICU patients who had undergone open cholecystectomy due to AAC during the years 2000–2001 and 2003–2004 were examined for clinical and organ failure data. The indication for open cholecystectomy was a suspicion of AAC based on clinical signs and symptoms of sepsis or deteriorating multiple organ dysfunction without other obvious foci and/or radiological (computed tomography or ultrasound) findings indicative of cholecystitis. A total of 73 patients had operatively treated AAC during the study periods, giving an incidence of 0.9% of all admissions (73/8184) and an incidence of 6.7% among the long-stayers (ICUstay >5 days). The hospital mortality of these patients was 43%. Infection was the most common admission diagnosis followed by cardiovascular surgery. The patients were severely ill, the mean (SD) APACHE II score being 25.5 (6.4) and the mean (SD) SOFA score 10.2 (3.5) on admission. In those patients who had AAC as the only intra-abdominal complication of multiple organ dysfunction, cholecystectomy was followed by a remarkable improvement of individual and total SOFA scores by the seventh postoperative day. The AAC gallbladders were histologically and immunohistologically compared to normal gallbladders and to gallbladders of patients with acute calculous cholecystitis (ACC). The ACC patients were admitted into hospital because of primary acute gallbladder disease, were treated on a normal ward and did not have severe sepsis or multiple organ dysfunction. The typical histopathological features of AAC (34 cases) in the gallbladder wall were bile infiltration, lymphatic dilatation and leucocyte margination of blood vessels, while epithelial degeneration and defects, widespread occurrence of inflammatory cells and extensive and deep muscle layer necrosis were typical features of ACC (28 cases). Tight junction proteins (claudin-1, -2, -3, -4, occludin, ZO-1 and E-cadherin) were uniformly expressed in normal gallbladder epithelium, with the exception of claudin-2, which was present in less than half of the cells. In AAC, the expression of cytoplasmic occludin and claudin-1 was decreased compared to control group. In ACC, the expression of claudin-2 was increased, but the expression of claudin-1, -3 and -4, occludin and ZO-1 was decreased compared to normal or AAC gallbladders. In conclusion, AAC is associated with severe illness, infection, long intensive care unit stay and deteriorating multiple organ dysfunction. Open cholecystectomy is one important contributing factor to reverse the course of multiple organ dysfunction in these patients. Histological and immunohistological studies suggest that AAC is a manifestation of systemic inflammatory disease, while ACC is a local inflammatory and often infectious disease.