Helicobacter pylori infection (HPI) imposes substantial social costs and is of major etiological importance in peptic ulcer disease, gastric cancer, and accelerated cardiovascular diseases. This study determined the risk of acute coronary syndrome (ACS) associated with HPI in a nationwide retrospective cohort study. By using the Taiwan National Health Insurance Research Database (NHIRD), we identified patients diagnosed with HPI from 1998 to 2010. In addition, we randomly selected non-HPI controls frequency-matched by age, sex, and index year from the general population free of HPI. The risk of ACS was analyzed using Cox proportional hazards regression models in which sex, age, and comorbidities were included as variables. We identified 17,075 participants for the HPI group and selected 68,300 participants for the comparison group. The incidence rates were increased in the patients in the HPI group compared with those in the comparison group. Overall, the HPI patients exhibited a 1.93-fold high crude hazard ratio for ACS, and a 1.48-fold adjusted hazard ratio after age, sex, and comorbidities were adjusted. However, the overall adjusted hazard ratio of ACS increased with increasing age with a 3.11 to 8.24 adjusted hazard ratio among the various age groups. Several comorbidities, such as diabetes, hyperlipidemia, and COPD exhibited synergistic effects for ACS risk. We determined a significant association between ACS and comorbidities and provide evidence to encourage clinicians to observe ACS-related comorbidities.