Gastric cancer (GC) is the result of a long multi-step and multifactorial process involving possible interactions between Helicobacter pylori infection, environmental exposures and host genetic susceptibility. Interactions between H. pylori infection, tobacco smoking and dietary antioxidants are biologically plausible. Positive interactions between risk factors imply that, in certain subgroups of the population, the risk of GC associated with simultaneous exposure to these factors is higher than that in the rest of the population, and these subgroups have to be the target for preventive measures. Using PubMed, we reviewed all studies published in English up to December 2008 carried out in humans on interactions between H. pylori infection and smoking exposure and between H. pylori infection and dietary factors in gastric carcinogenesis. Although relatively few epidemiological studies have evaluated the effect of the interaction between smoking and H. pylori infection on GC risk, there is a suggestion of a positive interaction between the two factors. In contrast, evidence suggests a negative interaction between dietary antioxidants and H. pylori infections on GC risk. The potential protective effect of dietary antioxidants such as vitamins C and E and beta-carotene seems to be stronger in those infected by H. pylori, even though results are inconsistent. In Asian populations, subjects infected by H. pylori and with high dietary salt intake may have a higher risk of GC than subjects without H. pylori infection and with a low salt intake. The risk of GC associated with red meat, processed meat or endogenous formation of nitrosamines appears to only be observed in subjects infected by H. pylori. More and larger epidemiological studies, mainly prospective studies, are necessary to reach a more definitive conclusion on these interactions.