Over the past several decades, significant advances have been made in the primary and secondary prevention of coronary artery disease. However, effects of changing lifestyle and treatment practices on demographic and clinical profiles and on hospital outcomes of patients who present with acute myocardial infarction (AMI) have not been well characterized. We carried out a prospective population-based investigation of >25-year trends (1975 to 2001) in demographic and clinical characteristics, treatment practices, and hospital outcomes of patients who had been hospitalized with AMI. Residents of a metropolitan area (Worcester, Massachusetts) who had been hospitalized with validated AMI (n = 10,440) in all greater Worcester hospitals during thirteen 1-year periods between 1975 and 2001 comprised the sample of interest. Patients who had been hospitalized during the most recent study years were significantly older, were more likely to be women, and had a greater prevalence of co-morbidities. Hospitalized patients were increasingly more likely to receive effective cardiac medications and coronary interventions over the period under investigation. Multivariable-adjusted hospital survival rates improved considerably over time, whereas different trends were observed in the occurrence of several important clinical complications. The present results provide insights into the changing characteristics of patients who are hospitalized with AMI, treatment practices, and their short-term outcomes. Given the magnitude of AMI and evolving approaches to manage it, continued monitoring of these trends remains of considerable clinical and public health importance.