Background : Gastric cancer is the second highest cause of cancer mortality in the world, despite declining rates of incidence in many industrialized countries. We carried out a case-control study to evaluate whether polymorphisms of DNA repair and glutathione S-transferase ( GST ) genes modulate the risk of developing diffuse gastric cancer. Methods : ERCC1 118 T/C, XRCC1 399 G/A, XPD 312 G/A, XPD 751 A/C, XRCC3 241 C/T, MS 919 A/G, GSTP1 105 A/G, GSTM1 -null/positive and GSTT1 -null/positive genotypes were obtained for a series of 126 Helicobacter pylori -negative diffuse gastric cancer patients and 144 Helicobacter pylori -negative controls sampled from the population of Marche, an area with high gastric cancer risk in central Italy. Results : GSTP1 105 A/G and GSTP1 105 G/G genotypes were identified as protective factors, with odds ratio (OR) of 0.4 (95% CI 0.17–0.81, p=0.01) and OR=0.58 (95% CI 0.33–1, p=0.05), respectively. GSTT1 -null genotype was identified as a protective factor, with OR=0.48 (95% CI 0.22–0.99, p=0.04). There was no significant difference between cases and controls for XPD 751 A/C, ERCC1 118 T/C, XRCC3 241 C/T, XRCC1 399 G/A, XPD 312 G/A, GSTM1 -null/positive and MS 919 A/G polymorphisms. Conclusions : This study suggests that GSTP1 105A/G and GSTT1 -null/positive genotypes might be associated with a reduced risk for sporadic diffuse gastric cancer. Clin Chem Lab Med 2007;45:822–8.