P73, a p53 homolog, has some p53-like activities and plays an important role in modulating cell cycle, apoptosis and DNA repair. The two linked polymorphisms in the non-coding region of exon2 of p73 gene, named G4C14-A4T14, may alter translation efficiency of the gene. The transcription of p73 gene is initiated by three promoters, termed P1-P3. There is a single nucleotide substitution (-386G/A) in the P3 promoter region with unknown function. To test the hypothesis that the genetic variations in the exon2 and P3 promoter play a role in the etiology of esophageal squamous cell carcinoma (ESCC), we conducted a population-based case-control study in 348 ESCC patients and 583 healthy controls from a high incidence region of Hebei province, China. The p73 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 (the age, sex and smoking status adjusted OR = 2.02, 95% CI = 1.54-2.67). The overall distribution of the p73 genotype, allelotype and haplotype in cancer patients and controls were not significantly different (all P-values are above 0.05). Stratification analysis by smoking status and family history of UGIC also did not show the significant influence of the polymorphisms on the risk of ESCC development. The results suggested that the p73 exon2 G4C14-A4T14 and P3 promoter -386G/A polymorphisms might not be used as potential markers to predicate the risk of ESCC development in northern China.