The etiology of necrotizing enterocolitis (NEC) is uncertain. We have hypothesized that subclinical intestinal ischemia might result in increased mucosal permeability to intraluminal toxins or bacteria, resulting in inflammation and NEC. In order to pursue this hypothesis, we designed a series of studies to investigate whether the first assumption is correct, ie whether a subclinical ischemia-reperfusion injury (IRI) results in increased mucosal permeability. Using a model of superior mesenteric artery occlusion (SMAO) in weanling rats, we initially defined 10-minute SMAO as "subclinical" IRI (ie, 100% survival, no histological changes, and no hemodynamic instability). Mucosal permeability to a standard probe molecule (51Cr EDTA) was then measured after sham operation, or 2-minute or 10-minute SMAO. There was an early increase in permeability 30 minutes after reperfusion in the 10-minute SMAO group, which was completely reversed by 2 hours. Further studies suggested that having passed through the mucosa, the probe entered the systemic circulation via both portal venous and intestinal lymphatic routes. Subclinical intestinal IRI results in an early, reversible increase in mucosal permeability to 51Cr EDTA, which may be important in the pathogenesis of NEC. Further studies are required to fully characterize this phenomenon, and to determine the mechanisms by which it occurs.