Abstract: Objective: PTEN, a tumor suppressor gene with lipid and protein phosphatase activities, plays an important role in regulating cell growth, proliferation, and apoptosis. An insertion polymorphism in intron 4 of the PTEN gene ⅣS4 (-/+), by a different splice variant that influences the expression of PTEN. This study was designed to investigate the association of this common polymorphism with the risk of esophageal squamous cell cancer (ESCC) in a high incidence region of Hebei province. Methods: We conducted a population-based case-control study in 350 ESCC patients and 634 healthy controls. The PTEN genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The results showed that a family history of upper gastrointestinal cancer(UGIC) significantly increased the risk of ESCC(age, sex and smoking status were adjusted; OR= 1.73, 95% CI=1.29-2.32). The overall distribution of the PTEN ⅣS4 genotype was not significantly different between cancer patients and the controls. Compared with the PTEN ⅣS4-/- genotype, the PTEN ⅣS4+/+ genotype significantly decreased the risk of developing ESCC (adjusted OR=0.64, 95% CI=0.44-0.94). Stratification analysis by smoking status and family history of UGIC revealed that the PTEN ⅣS4-/+ genotype reduced the risk of ESCC(adjusted OR=0.55, 95% CI=0.34-0.90) among subjects with UGIC family history. Alternatively, the PTEN IVS4-/+ and PTEN IⅣS4+/+ genotype did not showa significant effect on the risk of ESCC among smokers, non-smokers and subjects without UGIC family history. Conclusion: Our results suggested that the PTEN IVS4+/+ homozygous genotype plays a protective role in the development of ESCC in a high incidence region of Hebei province. In addition, the PTEN IVS4-/+ genotype only reduced the risk of familial ESCC.