Few studies have explored hospitalization outcome differences between patients who are seropositive for human immunodeficiency virus (HIV) compared to HIV-seronegative patients with acute myocardial infarctions (AMIs). The aim of this study was to explore in-hospital AMI mortality risk in seropositive and seronegative patients. A secondary analysis of the Nationwide Inpatient Sample from 1997 to 2006 was conducted. This sample allows the approximation of all United States hospitalizations. All AMI encounters with and without co-occurring HIV were identified using appropriate International Classification of Diseases and procedure codes. Descriptive and Cox proportional-hazards analyses were then conducted to estimate mortality differences between seropositive and seronegative patients while adjusting for demographic, clinical, hospital, and care factors. The results demonstrated higher AMI hospitalization mortality hazard in seropositive compared to seronegative patients after adjustment for age, gender, ethnicity, medical co-morbidities, hospital type, and number of in-hospital procedures (HR 1.38, 95% confidence interval 1.01 to 1.87, p = 0.04). Stratified analysis demonstrated greater although not statistically significant mortality hazard for non–ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction in seropositive compared to seronegative patients. Typical AMI care procedures occurred at significantly lower rates in seropositive versus seronegative patients, including thrombolytic and anticoagulant agents (18% vs 22%), coronary arteriography (48% vs 63%), left cardiac catheterization (52% vs 66%), and coronary artery bypass graft (6% vs 14%). In conclusion, additional mortality burden and lower procedure rates occur for HIV-seropositive patients receiving AMI care. Health care providers should be alert to the increased mortality burden when treating seropositive patients with AMI.