Objective While some studies have evaluated the prescribing patterns of clopidogrel in combination with proton-pump inhibitors (PPI) before and after the FDA safety communication, none have assessed the prescribing patterns of histamine-2 receptor antagonists (H2RAs), one alternative to PPIs, during the same time period. This study aims to assess the trends in the concomitant use of clopidogrel with H2RAs or PPIs between 2007 and 2014 using the National Health and Nutrition Examination Survey (NHANES) database. Methods This was a secondary data analysis of survey participants who reported being 20 years of age or older and taking clopidogrel at the time of survey interview. The primary outcomes measured were the independent use of H2RAs or PPIs over 2007-2014. Logistic regression analyses compared H2RA and PPI use over time, while controlling for sociodemographics, insurance coverage, history of cardiovascular disease and history of smoking. Key findings 7.5% of study participants were on H2RAs while 26.3% were on PPIs. Except for the use of private health insurance, there were no statistical differences in covariates across the study period. H2RA use increased numerically from 2007 to 2014 by 5.6 percentage points (P = 0.118). PPI use decreased numerically from 2007 to 2010 by 5.9 percentage points but increased thereafter by 6 percentage points through 2014 (P = 0.488). The use of pantoprazole significantly increased (P = 0.005) while the use of lansoprazole significantly decreased (P = 0.008). The use of other PPIs over time did not change significantly (P > 0.05).Conclusions Overall H2RA and PPI use did not change among adults taking clopidogrel from 2007 through 2014. Prescribers must consider acid reducing agents that will not interact with clopidogrel. Future studies should evaluate the use of PPIs and H2RAs with dual antiplatelet therapy and in patients with a high risk of gastrointestinal bleeding.