Over recent years, genome-wide association studies have contributed to our understanding of genetic susceptibility to sporadic cancer. In this study, we assessed the association between upper gastrointestinal cancer risk and four genome-wide association studies-identified single nucleotide polymorphisms (SNPs), implicated earlier in prostate and colorectal cancer susceptibility. Genotyping for each SNP was performed in two independent Caucasian population-based case-control studies. The first study comprised 290 gastric cancer cases and 374 controls. The second study included 185 noncardia gastric cancers, 123 cardia cancers, 158 oesophageal cancers and 209 controls. Odds ratios (ORs) were computed from logistic models and adjusted for potential confounding variables. An inverse association was observed between the SNP rs1447295, located at 8q24, and gastric cancer risk in the first study population (OR=0.63; 95% confidence interval: 0.41-0.97). A positive association was observed for the same SNP and oesophageal squamous cell carcinoma in the second study population (OR=7.43; 95% confidence interval: 1.37-49.98). No significant associations were detected in either study for the three remaining SNPs (rs6983297, rs10505477 and rs719725). Our data represent novel findings on heritable susceptibility to gastric and oesophageal cancer and warrant validation in additional populations.