Sepsis and hemorrhage can result in injury to multiple organs and is associated with an extremely high rate of mortality. We hypothesized that peritoneal negative pressure therapy (NPT) would reduce systemic inflammation and organ damage. Pigs (n = 12) were anesthetized and surgically instrumented for hemodynamic monitoring. Through a laparotomy, the superior mesenteric artery was clamped for 30 min. Feces was mixed with blood to form a fecal clot that was placed into the peritoneum, and the abdomen was closed. All subjects were treated with standard isotonic fluid resuscitation, wide spectrum antibiotics, and mechanical ventilation, and were monitored for 48 h. Animals were separated into two groups 12 h (T12) after injury: for NPT (n = 6), an abdominal wound vacuum dressing was placed in the laparotomy, and negative pressure (-125 mmHg) was applied (T12 - T48), whereas passive drainage (n = 6) was identical to the NPT group except the abdomen was allowed to passively drain. Negative pressure therapy removed a significantly greater volume of ascites (860 ± 134 mL) than did passive drainage (88 ± 56 mL). Systemic inflammation (e.g. TNF-α, IL-1β, IL-6) was significantly reduced in the NPT group and was associated with significant improvement in intestine, lung, kidney, and liver histopathology. Our data suggest NPT efficacy is partially due to an attenuation of peritoneal inflammation by the removal of ascites. However, the exact mechanism needs further elucidation. The clinical implication of this study is that sepsis/trauma can result in an inflammatory ascites that may perpetuate organ injury; removal of the ascites can break the cycle and reduce organ damage.