Abstract Aim We investigated temporal trends in major cardiovascular events following first-time myocardial infarction (MI) and trends in revascularization and pharmacotherapy from 2000 to 2017. Methods and results Using nationwide registries, we identified 120 833 Danish patients with a first-time MI between 2000 and 2017. We investigated 30-day and 1-year mortality and the 1-year risk of first-time admission for heart failure (HF) and recurrent MI. Patients were younger with a higher prevalence of hypertension and diabetes in 2015–2017 compared with 2000–2002. The patients were predominantly male (65.6%), and the median age declined by 3 years through the periods. Percutaneous coronary interventions within 7 days after first-time MI increased significantly (2000: 11.4% vs. 2017: 68.6%; Ptrend < 0.001). Cardiovascular medication after first-time MI changed significantly in the same period. Absolute risks and adjusted rates of outcomes were significantly lower in 2015–2017 compared with 2000–2002: 30-day mortality: 6.5% vs. 14.1% [hazard ratio (HR) 0.52, 95% confidence interval (CI): 0.48–0.55); 1-year mortality 10.7% vs. 21.8% (HR 0.52, 95% CI: 0.50–0.55); recurrent MI: 4.0% vs. 7.8% (HR 0.56, 95% CI: 0.51–0.62); and first-time admission for HF: 2.9% vs. 3.7% (HR 0.82, 95% CI: 0.73–0.92). The rates of 30-day/1-year mortality and recurrent MI showed significantly decreasing trends (Ptrend < 0.001). The rates of first-time admission for HF were borderline significant (Ptrend = 0.045). Conclusion From 2000 to 2017, we observed a decreasing risk of recurrent MI, first-time admission for HF, and all-cause mortality in patients with a first-time MI. In the same period, we observed a high rate of guideline-recommended pharmacological treatment after first-time MI as well as increasing rate of early revascularization in Denmark. Translational perspectives The results from the current study portrait the risk of all-cause mortality, recurrent MI, and first-time admission for HF in a real-life setting with a very high utilization of early revascularization and guideline-recommended pharmacological therapy. We observed a temporal trend of improved survival, reduced risk of recurrent MI, as well as reduced risk of first-time admission for HF after first-time MI from 2000 through 2017. We observed an increase in the overall use of revascularization, as well as early revascularization and use of guideline-recommended pharmacotherapy. Our study reveals important results from real-life, nationwide data, showing a reduced risk of cardiovascular outcomes after first-time MI during the past 20 years. Current guidelines are based on results from clinical trials. Our real-life results add additionally important knowledge on patients’ prognosis after first-time MI and underline the importance of treating MI according to guideline recommendations.