SUMMARY.  PTEN, as a tumor suppressor gene, plays an important role in regulating cell growth, proliferation, and apoptosis. Two common polymorphisms, –9C/G and IVS4 (−/+), may alter susceptibility to the disease. To test the hypothesis that the genetic variations of PTEN play a role in the etiology of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA), a population‐based case‐control study was conducted in 350 ESCC patients, 257 GCA patients, and 634 healthy controls from a high‐incidence region of Hebei province, China. The PTEN polymorphisms were genotyped by polymerase chain reaction‐restriction fragment length polymorphism analysis (PCR‐RFLP). The results showed that the family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing ESCC and GCA (the age, gender and smoking status adjusted OR = 1.73 and 1.67; 95% CI = 1.29–2.32 and 1.28–2.19, respectively). The overall distribution of the PTEN –9C/G genotype was not significantly different between cancer patients and controls. Compared with the PTEN IVS4‐/− genotype, the IVS4+/+ genotype significantly decreased the risk of ESCC and GCA development, the adjusted OR was 0.64 (95% CI = 0.44–0.94) and 0.63 (95% CI = 0.41–0.98), respectively. Stratification analysis by gender, age, smoking status and family history of UGIC showed that the PTEN IVS4−/+ genotype only reduced the risk of ESCC (adjusted OR = 0.55, 95%CI = 0.34–0.90) among subjects with family history of UGIC. While the IVS4+/+ genotype decreased the susceptibility to both ESCC and GCA (adjusted OR = 0.61 and 0.57, 95% CI = 0.37–0.98 and 0.34–0.98, respectively) among male subjects, the IVS4+/+ genotype only decreased the risk of ESCC development among subjects younger than 55 years (adjusted OR = 0.43, 95% CI = 0.21–0.85). In addition, the haplotype analysis found that the –9C/IVS4– haplotype increased the risk of developing ESCC and GCA (OR = 1.31 and 1.24, 95% CI = 1.08–1.58 and 1.001–1.53). Our results suggested that the PTEN IVS4+/+ homozygote may play a protective role in the development of ESCC and GCA, while the haplotype –9C/IVS4– might be the risk factor of the development of ESCC and GCA in the high incidence region population of Hebei province, China.