Gastric carcinogenesis is a multifactorial process involving host gene and environmental interactions. Diverse case-control studies using different types of controls addressed the familial aggregation role for gastric cancer development. Our aim is to discuss the advantages and expected bias according to the different type of eligible controls. A PubMed search of papers on a query on first degree relatives of gastric cancer patients was conducted. The retrieved studies were evaluated regarding quality based on STROBE checklist. Data concerning risk of premalignant lesions and Helicobacter pylori infection was retrieved as the type of controls used on each study. Nine case-control studies were selected. A variety of controls were used ranging from general population to dyspeptic patients and spouses of the cases. We have observed that, independently of the type of control, the risk for the prevalence of premalignant lesions and H. pylori infection was higher for the cases. However, all of the evaluated case-control studies were average quality studies (mean 28 out of 45), with a small number of cases and controls (range from 39 to 300). Furthermore, concerning gene-environment interaction, each of the discussed type of control (general population, dyspeptic, spouse and neighbor) has potential advantages and disadvantages. The current data suggests that selection of any type of the aforementioned controls is feasible and seems to be mainly related to the feasibility of recruitment more than the genetic or environmental backgrounds. General population and dyspeptic patients would be equally appropriate for studies on familial aggregation of gastric cancer. Nevertheless, high-quality cohort studies are needed to validate this assumption.