Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) protects the intestines from injury in experimental necrotizing enterocolitis (NEC). We hypothesized that polymorphisms in the HB-EGF gene lead to low HB-EGF production in peripheral blood and increased risk of NEC in the Chinese Han population. To test this hypothesis, 30 NEC patients and 80 control subjects were selected. Five HB-EGF single-nucleotide polymorphisms (SNPs) and its plasma levels were measured by genotyping and enzyme-linked immunosorbent assay, respectively. Only 1 out of the 5 SNPs showed a notable result. The notable SNP (rs4912711) was associated with NEC in its minor allele frequency and its “G/T” genotype distribution. In addition, plasma HB-EGF levels were reduced especially the “G/T” genotype in NEC patients. Our data suggest that if validated in larger studies screening for HB-EGF SNPs/genotypes and plasma levels may be useful as a risk factor for NEC in the future.