Objective To investigate the effect of cimetidine on intestinal epithelial integrity and the calmodulin- dependent protein kinase IV ( CaMKIV) / cyclic AMP ( cAMP ) response element modulator ( CREM ) pathway in necrotizing enterocolitis (NEC). Methods Rats were divided into a control group, model group, cimetidine group, and CaMKIV inhibitor group. Except for the control group, the NEC newborn rat model was established by hypoxia + reoxygenation + cold stimulation on the first day of birth in each group over 3 consecutive days. After daily cold stimulation, 30. 5 mg / kg cimetidine was injected intravenously in the cimetidine group. In the CaMKIV inhibitor group, 0. 72 mg / kg of the CaMKIV inhibitor, kn62, was administered by intubation, and the control group and model group were treated with normal saline for the same number of days. The rats were then observed clinically. Intestinal permeability was measured by the fluorescein isothiocyanate-dextran ( FITC-dextran) tracing method ; hematoxylin eosin ( HE) staining was used to observe the histopathological changes of the intestinal tract; the concentrations of platelet activating factor ( PAF) and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA); and the protein levels of CaMKIV and CREM were detected by Western blot. Results In the model group, we observed decreased activity and slow responses, low appetite, and change of stool shape. The intestinal wall was thickened and edematous, with poor elasticity and some perforation, microscopically; the submucosa or lamina propria were markedly separated; villi were missing; and glands were disordered. Compared with the activity in the model group, activity in the cimetidine group and CaMKIV inhibitor group increased, and appetite was moderate; the intestinal wall was thickened and edematous, microscopically; and the submucosa or lamina propria were partially separated, with some partially denuded villi. Compared with the control group, the FITC-dextran levels, histological scores, and the levels of PAF, TNF-α, CaMKIV, and CREM proteins in the intestinal tissue of the model group mice were higher (P< 0. 05). Compared with the model group, the levels of FITC- dextran, histological scores, and the concentrations of PAF, TNF-α, and CaMKIV and CREM proteins in the intestinal tissue in the cimetidine group and CaMKIV inhibitor group were lower ( P< 0. 05). Conclusions Cimetidine may alleviate inflammation in NEC and improve the intestinal epithelium by inhibiting the CaMKIV/ CREM pathway, which may protect NEC newborn rats.