Numerous clinical trials using anti-inflammatory agents for patients with acute respiratory distress syndrome (ARDS) have failed despite efficacy in acute animal models. This underscores the necessity of developing a clinically relevant model of ARDS. Initially, we attempted to induce lung injury in pigs by fecal peritonitis only. When this was unsuccessful, we designed a two-hit model of ischemia/reperfusion (I/R) injury followed by fecal peritonitis to create a clinically applicable model of ARDS. The initial study consisted of Yorkshire swine [group 1, fecal clot (FC), n = 4] that were followed clinically after intraperitoneal placement of a fecal (0.5 mL/kg) blood (2 mL/kg) clot. Blood was sampled daily for cultures, a complete blood count, a lactate level, and various cytokine expression determined by enzyme-linked immunosorbent assay (ELISA). Pigs were treated with antibiotics and fluids, placed on a ventilator before sacrifice to obtain hemodynamic and pulmonary parameters, and underwent histologic lung assessment. Additionally, bronchoalveolar lavage fluid was obtained for protein concentration and cytokine levels. Once it was evident that no lung injury had occurred, we designed a more severe model. A second group of Yorkshire swine [group 2, superior mesenteric artery (SMA) + FC, n = 4] underwent SMA occlusion for 30 min (I/R) followed by intraperitoneal placement of a FC as in the initial group. These pigs were monitored more invasively and continuously in an intensive care setting for 48 h and followed, treated, and assessed in a similar fashion to group 1. Group 1 (FC) pigs survived 9 days and showed signs of sepsis (bacteremia with polymicrobial organisms), an inflammatory response in the form of elevated cytokines, yet no physiologic or histologic evidence of lung injury. Group 2 (SMA + FC) pigs demonstrated more severe sepsis, a significantly increased cytokine response compared with animals in the FC group, and physiologic signs of progressive pulmonary injury. Pigs in the SMA + FC group were sacrificed at 48 h after clinical deterioration (significant decline in oxygenation) and demonstrated pathologic evidence of lung injury indicated by increased bronchoalveolar lavage fluid protein, diffuse and thickened alveolar septae, hyaline membrane formation, and pulmonary edema. The addition of a second "hit" (SMA occlusion, I/R) to a FC sepsis model resulted in severe lung injury that developed within a 3-day period. To our knowledge, this is the first large animal experiment that definitively and consistently causes insidious onset ARDS in pigs. By closely paralleling the clinical development of pulmonary injury, this model should prove invaluable in the study of human ARDS.