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Background Proton pump inhibitors (PPIs) are recommended by the latest guidelines to reduce the risk of bleeding in acute myocar?dial infarction (AMI) patients treated with dual antiplatelet therapy (DAPT). However, previous pharmacodynamic and clinical studies have reported controversial results on the interaction between PPI and the P2Y12 inhibitor clopidogrel. We investigated the impact of PPIs use on in-hospital outcomes in AMI patients, aiming to provide a new insight on the value of PPIs. Methods A total of 23,380 consecutive AMI patients who received clopidogrel with or without PPIs in the China Acute Myocardial Infarction (CAMI) registry were analyzed. The pri?mary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE) defined as a composite of in-hospital cardiac death,re-infarction and stroke. Propensity score matching (PSM) was used to control potential baseline confounders. Multivariate logistic regres?sion analysis was performed to evaluate the effect of PPIs use on MACCE and gastrointestinal bleeding (GIB). Results Among the whole AMI population, a large majority received DAPT and 67.5％ were co-medicated with PPIs. PPIs use was associated with a decreased risk of MACCE (Before PSM OR: 0.857,95％ CI: 0.742-0.990, P = 0.0359; after PSM OR: 0.862,95％ CI: 0.768-0.949, P = 0.0245) after multi?variate adjustment. Patients receiving PPIs also had a lower risk of cardiac death but a higher risk of complicating with stroke. When GIB occurred, an alleviating trend of GIB severity was observed in PPIs group. Conclusions Our study is the first nation-wide large-scale study to show evidence on PPIs use in AMI patients treated with DAPT. We found that PPIs in combination with clopidogrel was associated with decreased risk for MACCE in AMI patients, and it might have a trend to mitigate GIB severity. Therefore, PPIs could become an available choice for AMI patients during hospitalization.