<b><i>Background/Purpose:</i></b> Cardiac tamponade is a medical emergency situation associated with a high rate of life-threatening complications, even after immediate interventions. Our aim was to characterize the acute inflammatory consequences of this event in a clinically relevant large animal model. <b><i>Methods:</i></b> Cardiac tamponade was induced for 60 min in anesthetized, ventilated and thoracotomized minipigs by intrapericardial fluid administration, the mean arterial pressure (MAP) being maintained in the interval of 40-45 mm Hg (n = 8). A further group (n = 7) served as sham-operated control. The global macrohemodynamics, including the right- and left-heart end-diastolic volumes (RHEDV and LHEDV), the pulmonary vascular resistance index (PVRI) and the superior mesenteric artery (SMA) flow, were monitored for 240 min, and the intestinal microcirculatory changes (pCO<sub>2</sub> gap) were evaluated by indirect tonometry. Blood samples were taken for the determination of cardiac troponin T and vasoactive inflammatory mediators, including histamine, nitrite/nitrate, big-endothelin, superoxide and high-mobility group box protein-1 levels in association with intestinal leukocyte and complement activation. <b><i>Results:</i></b> The cardiac tamponade induced significant decreases in MAP, cardiac output, LHEDV and SMA flow, while the PVRI and the pCO<sub>2</sub> gap increased significantly. After the removal of fluid from the pericardial sac, the MAP and the LHEDV were decreased, while the PVRI and the pCO<sub>2</sub> gap remained elevated when compared with those in the sham-operated group. In the posttamponade period, the abrupt release of inflammatory mediators was accompanied by a significant splanchnic leukocyte accumulation and complement activation. <b><i>Conclusions:</i></b> The macrocirculatory and splanchnic microcirculatory disturbances were accompanied by a significant proinflammatory reaction; endothelin and the complement system may be significant components of the inflammatory cascade that is activated in this porcine model of pericardial tamponade
