Intestinal differentiation, mediated by CDX2, may occur both in intestinal and in diffuse gastric carcinomas. In an attempt to ascertain the environmental determinants of the intestinal differentiation pathway, we aimed to compare the exposure to environmental factors in gastric cancer cases according to the CDX2 expression status. We evaluated 270 patients undergoing gastrectomy due to gastric adenocarcinoma. Cases were classified according to tumour location within the stomach, Laurén's histological type and CDX2 expression. Participants completed a comprehensive structured questionnaire on sociodemographic and behavioural characteristics and provided a blood sample for assessment of Helicobacter pylori infection status. Odds ratios with 95% confidence intervals were computed by unconditional logistic regression to compare cancer cases according to histological type and CDX2 expression status. Approximately 80% of the patients expressed CDX2, regardless of the histological type and location of the tumour. No statistically significant or consistent associations between sociodemographic or environmental exposures and CDX2 expression status were observed, except for a decreased risk of CDX2 expression in those with higher coffee consumption for tumours of the intestinal type (≥ 1 vs. <1 cup/day: odds ratio =0.36, 95% confidence interval: 0.13-0.97). In conclusion, this is the first study to use CDX2 expression as a finer marker of intestinal differentiation to distinguish aetiologically distinct subgroups of gastric cancer, adding new evidence to the previous research on the determinants of cancer of Laurén's intestinal and diffuse types.