Genetic variations in MDM2, PTEN and P53 might be involved in cancer susceptibility. To assess the contribution of polymorphisms in these three genes to the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population, we genotyped MDM2 T309G, Del1518, PTEN rs701848, rs2735343 and P53 Arg72Pro polymorphisms using PCR-restriction fragment length polymorphism analysis in 226 ESCC cases and 226 cancer-free controls. Here we showed that the risk of ESCC was elevated in subjects with any of the variant genotypes of PTEN rs2735343 and P53 Arg72Pro polymorphisms, but not any genotype of MDM2 or PTEN rs701848. Moreover, multiplicative interactions were observed between PTEN rs2735343 and P53 Arg72Pro or smoking status on risk of ESCC. Our study firstly indicated that PTEN rs2735343 might be a susceptibility factor for ESCC and reaffirmed the role of P53 Arg72Pro in ESCC in this Chinese population, but did not replicate the positive association between MDM2 T309G and ESCC found previously.