Treatment of acute ST-segment elevation myocardial infarction (STEMI) has dramatically changed over the past 2 decades. The goal of this study was to determine trends in the mortality of patients with acute STEMIs in the United States over a 16-year period (1988 to 2004) on the basis of gender, race, infarct location, and co-morbidities. The Nationwide Inpatient Sample database was used to analyze the age-adjusted mortality rates for STEMI from 1988 to 2004 for inpatients age >40. International Classification of Diseases, Ninth Revision, Clinical Modification codes consistent with acute STEMI were used. The Nationwide Inpatient Sample database contained a total of 1,316,216 patients who had diagnoses of acute STEMIs from 1988 to 2004. The mean age of these patients was 66.92 ± 12.82 years. A total of 163,915 hospital deaths occurred during the study period. From 1988, the age-adjusted mortality rate decreased gradually for all acute STEMIs for the entire study period (in 1988, 406.86 per 100,000, 95% confidence interval 110.25 to 703.49; in 2004, 286.02 per 100,000, 95% confidence interval 45.21 to 526.84). Furthermore, unadjusted mortality decreased from 15% in 1988 to 10% in 2004 (p <0.01). This decrease was similar between the genders, among most ethnicities, and in patients with diabetes and those with congestive heart failure. However, women and African Americans had higher rates of acute STEMI-related mortality compared to men and Caucasians over the years studied. In conclusion, age-adjusted mortality from acute STEMIs has significantly decreased over the past 16 years, with persistent higher mortality rates in women and African Americans the study period.