Platelet-activating factor (PAF) is a potent phospholipid mediator with diverse physiologic and pathologic effects. Based on animal and human data, endogenous PAF initiates an intense inflammatory response in the local intestinal epithelium that results in apoptosis, necrosis, and clinical and pathological signs of NEC. Pretreatment of animals with PAF receptor blockade or the PAF-degrading enzyme PAF-acetylhydrolase (PAF-AH) protects against NEC in various models. Clinical trials in human preterm infants are needed to assess the efficacy of PAF-AH to prevent NEC in this high-risk population.