Clopidogrel is an antiplatelet agent indicated in the management of atherothrombotic conditions. Bleeding is a predictable adverse event associated with antiplatelet agents. While non-ulcerogenic; a major site of bleeding with clopidogrel is the gastrointestinal (GI) tract. The risk of GI bleeding with clopidogrel monotherapy is generally low; however, it increases with the presence of other risk factors such as aspirin use, advanced age, prior GI bleed, non-steroidal anti-inflammatory drugs, steroids and anticoagulants. In patients with a prior GI bleed, the risk of recurrence is high and strategies to prophylactically mitigate the risk should be implemented. In this review, evidence supporting the use of proton pump inhibitors to reduce the risk of recurrent GI bleed is discussed. Recommendations on an appropriate regimen to diminish the risk are provided.