Infective endocarditis (IE) remains a life-threatening disease, yet substantial variation in reported incidences of the disease exist. We aimed to conduct a contemporary, nationwide study of the temporal changes in incidence of IE. We included all Danish cases of first-time IE (1997-2017) using nationwide registries. Patients were grouped into three seven-year intervals (1997-2003, 2004-2010, 2011-2017). Crude annual incidence rates (IR) per 100,000 person-years (PY) were examined overall and per subgroups: age, sex, patients without prior prosthetic heart valve or a cardiac implantable electronic device (CIED). Incidence rate ratios (IRR) were calculated adjusting for age-group, sex and diabetes. We identified 8675 patients with IE. Over time, patients were older at diagnosis with a median age of 66.2 years (interquartile range, IQR: 51.5-76.5) and 72.2 years (IQR 62.2-79.9) in 1997-2003 and 2011-2017, respectively. The overall IR increased from 5.0/100,000 PY (95% CI: 4.4-5.6) to 10.5/100,000 PY (95% CI: 9.6-11.3) from 1997 to 2017. IR for patients without prior prosthetic heart valve or a CIED increased from 4.9/100,000 PY (95% CI: 4.3-5.5) to 6.4/100,000 PY (95% CI: 5.8-7.1) (P ≤ 0.0001 for interaction). The IR in males increased from 5.6/100,000 PY (95% CI: 4.7-6.5) to 14.2/100,000 PY (95% CI: 12.9-15.6). The IR in females increased from 4.3/100,000 PY (95% CI: 3.6-5.2) to 6.7/100,000 PY (95% CI: 5.8-7.7). IRR (adjusted for age-groups, sex and diabetes) increased over time (IRR = 1.60 (1.39-1.85) in 2017 vs 1997). The incidence of IE more than doubled during the study period. The increase was mainly seen among men and elderly patients only partly explained by the increase in patients with prior heart valve prosthesis or a CIED.