We compared the time course of histamine release with other markers of intestinal injury in a rabbit model of necrotizing enterocolitis. Injury was induced by luminal acetic acid (200 mM) and casein (10 mg/ml) and experiments terminated after 45 min or 3 hr. Compared to saline controls there was a significant elevation of epithelial permeability (51Cr-EDTA clearance) and luminal protein levels at both time points. Luminal fluid histamine levels were approximately 120-fold greater than saline controls at 45 min but were indistinguishable from control values at 3 hr. We conclude that although mast cell activation is a characteristic of this model, elevations in histamine levels are transient.