Researches showed that polymorphisms of p21(cip1) and p27(kip1) genes have associations with susceptibilities of breast cancer, lung cancer, prostate cancer, and so on. This study was to investigate the possible association of functional polymorphisms of p21(cip1) and p27(kip1) genes with susceptibilities of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in a population from a high incidence region in north China. The single nucleotide polymorphisms (SNPs) in the 3'-untranslated region of p21(cip1) gene and in codon 109 of p27(kip1) gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 299 ESCC patients, 256 GCA patients, and 437 healthy controls from a high incidence region of north China. The frequency of p21(cip1) T allelotype was significantly higher in ESCC patients than in healthy controls (42.8% vs. 36.7%, P=0.02). The frequency of p27(kip1) V allelotype was significantly higher in ESCC and GCA patients than in healthy controls (96.8% and 96.1% vs. 92.9%, P=0.001, P=0.02). The distribution of p21(cip1) genotypes among ESCC patients was significantly different from that among healthy controls (P=0.04); compared with the combination of the C/C and C/T genotypes, the T/T genotype significantly elevated the risk of developing ESCC [adjusted odds ratio (OR)=1.93, 95% confidence interval (CI)=1.12-3.94]. The distribution of p27(kip1) genotypes among ESCC and GCA patients were significantly different from that among healthy controls (P=0.002, P=0.01); compared with the combination of V/G and G/G genotypes, the V/V genotype significantly elevated the risk of developing ESCC and GCA (adjusted OR=2.44, 95% CI=1.21-4.02; adjusted OR=2.01, 95% CI=1.12-3.68). When stratified for smoking and family history of upper gastrointestinal cancers (UGIC), compared with the combination of V/G and G/G genetypes, the V/V genotype significantly elevated the risk of developing both ESCC and GCA in smokers (adjusted OR=2.24, 95% CI=1.14-4.03; adjusted OR=2.61, 95% CI=1.25-3.82) and ESCC in individuals with positive family history of UGIC (adjusted OR =2.04, 95% CI=1.04-3.43). The combination of p21(cip1) T/T and p27(kip1) V/V genotypes significantly elevated the risk of developing ESCC and GCA (adjusted OR=3.78, 95% CI=1.46-5.89; adjusted OR=2.56, 95% CI=1.06-4.78). In north China, p21(cip1) polymorphisms might be correlated with the susceptibility of ESCC, p27(kip1) polymorphisms might be correlated with the susceptibilities of ESCC and GCA, and they might have synergetic effect on ESCC and GCA development.