Lack of health insurance is associated with adverse clinical outcomes; however, association between health insurance status and outcomes in patients presenting with ST-elevation myocardial infarction (STEMI) is unclear. Using the Nationwide Inpatient Sample data from 2003 to 2014, hospitalizations with STEMI in patients 18 years of age and older were extracted. Based on health insurance status, patients were categorized into insured and uninsured groups. The primary outcome measure was in-hospital mortality. Adjusted analysis using inverse probability weighting with multivariable regression was performed to identify independent predictors of in-hospital mortality. Of 2,710,375 patients included in the final analysis, 220,770 patients were uninsured. Unadjusted in-hospital mortality was lower in uninsured patients (5.1% vs 9.3%; p <0.001). Adjusted analysis showed that lack of health insurance was associated with the worst in-hospital mortality (odds ratio [OR] = 1.77, 95% confidence interval [CI] 1.72 to 1.82; p <0.001). Other independent predictors of in-hospital mortality were low household income (OR = 1.08, 95% CI 1.07 to 1.09; p <0.001), acute stroke (OR = 2.87, 95% CI 2.80 to 2.95; p <0.001), acute kidney injury (OR = 2.60, 95% CI 2.57 to 2.64; p <0.001), cardiac arrest (OR = 8.88, 95% CI 8.77 to 8.99; p <0.001), cardiogenic shock (OR = 5.81, 95% CI 5.74 to 5.88; p <0.001), requirement of pericardiocentesis (OR = 10.54, 95% CI 9.64 to 11.52; p <0.001), gastrointestinal bleeding (OR = 1.41, 95% CI 1.38 to 1.54; p <0.001), and pneumonia (OR = 1.43, 95% CI 1.41 to 1.45; p <0.001). The multivariate model demonstrated good statistical discrimination (c-statistic = 0.89). In conclusion, lack of health insurance is independently associated with increased in-hospital mortality in patients presenting with STEMI.