Introduction: With new legislation becoming more lenient regulating recreational cannabis use in the United States, the prevalence of cannabis has doubled since 2002 and continues to rise. While there have been some reports of the benefits of cannabis, medical literature has identified several adverse cardiovascular events. Cannabis as a significant risk factor for the acute coronary syndrome (ACS) has been suspected to be attributed to vascular inflammation and platelet activation as well as elevation in heart rate and blood pressure through sympathetic stimulation. Methods: We conducted a case-control study utilizing the Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS) 2019 database to investigate hospitalizations for patients aged 18 years old or older with the primary diagnosis of ACS. Comorbidities were identified through their international classification of diseases, 10th revision (ICD-10 codes) recorded in the discharge record for each hospitalization. Records having cocaine or other stimulants were excluded. An alpha (p) value less than 0.05 was considered statistically significant. Results: Of the 34,948,093 records included in the study, 225,275 had a primary diagnosis of ACS, and 767,525 had evidence of cannabis use. The rate of cannabis use in the ACS group (2%, n= 4,490) was lower than the non-ACS group (2.2%, n=763,035, p<0.001), while the rate of smoking was higher in the ACS group [49.5% (n=111,405) vs 31.2% (n=10,840,496), p<0.001] . However, after adjusting for other cardiovascular risk factors in a multivariable logistic regression model, the odds of cannabis use were comparable to smoking (Table 1). Conclusions: In this retrospective case-control study, the odds of cannabis use were similar to the odds of smoking in the records with a primary admission diagnosis of ACS, highlighting cannabis as a strong potential cardiovascular risk factor. Prospective cohort studies are warranted to establish the causality.