Background: Socioeconomic, racial, and regional disparities have been associated with worse clinical outcomes among patients with coronary disease. We evaluated the association of income, race, and geographic variation and in-hospital mortality among acute myocardial infarction (AMI) admissions in the United States. Methods: We conducted a retrospective cohort study using the Nationwide Inpatient Sample from 2015 to 2019. A multi-level logistic regression model was used (with sampling weights) to investigate the association between in-hospital mortality and income quartiles by patient’s ZIP code, race, and hospital regions, while adjusting for hospital clustering, lifestyle factors, clinical history, and hospital-level factors. Results: A total of 2,798,225 hospitalizations (≥18 years) with a principal diagnosis of AMI were identified. In multivariable analysis, compared with the highest income quartile, residents in the lowest income quartile (OR=1.10 [1.08–1.13] P <0.001) or second lowest income quartile (OR=1.07 [1.05–1.09] P <0.001) had higher odds of in-hospital mortality. Compared with those identifying as White, Black (OR=0.89 [0.87–0.91] P <0.001) and Hispanic (OR=0.91 [0.88–0.93] P <0.001) groups had lower odds of mortality, while Asian or Pacific Islander (OR=1.07 [1.03–1.11] P <0.001), Native American (OR=1.11 [1.02–1.21] P <0.05), and Unspecified groups (OR=1.09 [1.05–1.13] P <0.001) had higher odds of mortality. Residents in the South had higher mortality than those in the Northeast (OR=1.06 [1.00–1.12] P <0.05). Conclusion: Our large contemporary study shows that lowest income residents, Whites, Asian or Pacific Islanders, and Native Americans and residents of South had higher in-hospital mortality compared with highest income residents, Blacks and Hispanics, and residents in the Northeast. Additional studies are needed to better understand the complex mechanisms that underpin disparities in outcomes among AMI patients.