Background. Literature regarding the influence of age/sex on mortality trends for acute myocardial infarction (AMI) hospitalizations is limited to hospitals participating in voluntary AMI registries. Objective. Evaluate the impact of age and sex on in-hospital AMI mortality using a nationally representative hospital sample. Methods. Secondary data analysis using AMI hospitalizations identified from the Nationwide-Inpatient-Sample (NIS). Descriptive and Cox proportional hazards analysis explored mortality trends by age and sex from 1997–2006 while adjusting for the influence of, demographics, co-morbidity, length of hospital stay and hospital characteristics. Results. From 1997–2006, in-hospital AMI mortality rates decreased across time in all subgroups (𝑃<.001), except for males aged <55 years. The greatest decline was observed in females aged <55 years, compared to similarly aged males, mortality outcomes were poorer in 1997-1998 (RR 1.47, 95% CI  =  1.30–1.66), when compared with 2005-2006 (RR 1.03, 95% CI  =  0.90–1.18), adjusted 𝑃 value for trend demonstrated a statistically significant decline in the relative AMI mortality risk for females when compared with males (<0.001). Conclusion. Over the last decade, in-hospital AMI mortality rates declined for every age/sex group except males <55 years. While AMI female-male mortality disparity has narrowed, some room for improvement remains.