Abstract Aims Little is known about the mortality for patients with infective endocarditis (IE) on a nationwide scale, and previous studies have been conducted in selected cohorts from tertiary centers. We aimed to investigate temporal trends in mortality using nationwide Danish registries. Methods and results We identified patients with first-time IE between 1999–2018, and they were grouped by calendar periods (1999–2003, 2004–2008, 2009–2013, 2014–2018). One-year mortality was estimated using Kaplan–Meier estimates. For calendar periods, odds ratios (ORs) and hazard ratios (HRs) were computed using multivariable adjusted logistic regression and Cox proportional Hazards analyses for in-hospital and one-year mortality, respectively. We identified 8804 patients with IE. Age and proportions of men were: 66.7 (25th–75th percentile: 53.4–76.7) years and 59.9% in 1999–2003 and 72.8 (25th–75th percentile: 63.4–80.3) and 65.8% in 2014–2018. In-hospital mortality was 1999–2003: 24.5%, 2004–2008: 22.8%, 2009–2013: 18.8%, and 2014–2018: 18.3%. Relative to 1999–2003, adjusted likelihoods of in-hospital mortality were: OR = 0.81 (95% CI: 0.69–0.96) in 2004–2008, OR = 0.59 (95% CI: 0.50–0.69) in 2009–2013, and OR = 0.51 (95% CI: 0.43–0.60) in 2014–2018. By calendar periods, crude risks of one-year mortality were: 34.4% (95% CI: 32.0–36.8%), 33.5% (95% CI: 31.5–35.6%), 32.1% (95% CI: 30.2–34.0%), and 33.1% (95% CI: 31.3–34.8%). Relative to 1999–2003, adjusted rates of one-year mortality were: HR = 0.88 (95% CI 0.79–0.99) in 2004–2008, HR = 0.76 (95% CI: 0.68–0.86) in 2009–2013, and HR = 0.72 (95% CI: 0.64–0.81) in 2014–2018. Conclusion In this nationwide study of patients with first-time IE between 1999–2018, both short- and long-term survival has improved over time when accounting for changes in patient characteristics. One-sentence Summary When accounting for patient characteristics, both short- and long-term mortality have improved in patients with first-time infective endocarditis.