BackgroundIn addition to Helicobacter pylori (H. pylori) infection eradication, some medications, including aspirin, metformin, and statins, have been suggested to have protective effects against gastric cancer (GC) development in observational studies. We launched the Ardabil gastric cancer randomized placebo-controlled prevention trial (AGCPT) to evaluate the effectiveness of long-term low-dose aspirin use for the prevention of development and mortality of GC after H. pylori eradication.Methods/designAGCPT is a prospective population-based double-blind, randomized clinical trial. The study sample was targeted at 21,000 participants aged from 35 to 70 years old, both sexes, in Ardabil, a province in northwest Iran with relatively high rates of GC incidence and mortality. All eligible participants were initially tested for H. pylori infection using a H. pylori stool antigen test. Participants with positive tests undergo H. pylori eradication by standard treatment regimens. All participants with a negative test and those with a positive test with a subsequent confirmed H. pylori eradication test were entered into the intervention phase. In the intervention phase, participants were allocated randomly into either the treatment (daily oral consumption of 81 mg enteric-coated aspirin tablets) arm or the control (placebo) arm using permuted balanced blocks. Subjects will be followed for an average period of 10 years to evaluate the incidence and mortality rates of GC.DiscussionIn addition to preventing other diseases like cardiovascular events, aspirin may prevent GC incidence and mortality. AGCPT will investigate the difference between the two study arms in the proportion of the cumulative incidence and mortality rates of GC. The study’s results may help policymakers and researchers update the strategies for GC prevention.Trial registrationThis trial with the registry name of “The effect of Low-dose Aspirin in the Prevention of Gastric Cancer” was registered in the Iranian Registry of Clinical Trials, IRCT.ir, under the identifier IRCT201105082032N3. Registered on April 21, 2017.