ABSTRACT To screen intestinal barrier genes associated with porcine epidemic diarrhea virus (PEDV) infection, in the present study we first detected PEDV-infected piglets ( Sus scrofa ) with intestinal damage using quantitative real-time PCR (qPCR) and hematoxylin and eosin (HE) staining. Then, we used qPCR to identify expression differences of intestinal barrier genes between the PEDV-infected and control groups. The results showed that the expression levels of most genes were significantly different between the two groups. Hierarchical clustering and correlation analysis were performed for the expression levels of 25 candidate genes to reveal the key gene that may be involved in PEDV resistance. Two important candidate genes, GLP2 (glucagon–like peptide 2) and AQP3 (aquaporin 3), have their expression positively correlated (r = 0.84). We speculated that decreased expression of GLP2 and AQP3 might play an important role in the process of PEDV infection of piglets by reducing the expression of tight junction proteins and disrupting the junctions between intestinal epithelial cells. There may be an underlying biological interaction between the two genes, which together affect the functional integrity of the intestinal barrier.