BACKGROUND: Patients with tetralogy of Fallot (ToF) are considered at high risk of infective endocarditis (IE) as a result of altered hemodynamics and multiple invasive procedures, including pulmonary valve replacement (PVR). Data on the long-term risk of IE are sparse. METHODS AND RESULTS: In this observational cohort study, all patients with ToF born from 1977 to 2018 were identified using Danish nationwide registries and followed from date of birth until occurrence of first-time IE, emigration, death, or end of study (December 31, 2018). The comparative risk of IE among patients with ToF versus age-and sex-matched controls from the background population was assessed. Because of rules on anonymity, exact numbers cannot be reported if the number of patients is <4. A total of 1164 patients with ToF were identified and matched with 4656 controls. Among patients with ToF, 851 (73.1%) underwent early surgical intracardiac repair and 276 (23.7%) underwent PVR during follow-up. During a median follow-up of 20.3 years, 41 (3.5%) patients with ToF (comprising 24 [8.7%] with PVR and 17 [1.9%] without PVR) and <4 (<0.8%) controls were admitted with IE. The incidence rates of IE per 10 000 person-years were 22.4 (95% CI, 16.5– 30.4) and 0.1 (95% CI, 0.01– 0.7) among patients and controls, respectively. Moreover, PVR was associated with a further increased incidence of IE among patients with ToF (incidence rates per 10 000 person-years with and without PVR were 46.7 [95% CI, 25.1– 86.6] and 2.8 [95% CI 2.0– 4.0], respectively). CONCLUSIONS: Patients with ToF are associated with a substantially higher incidence of IE than the background population. In particular, PVR was associated with an increased incidence of IE. With an increasing life expectancy of these patients, intensi-fied awareness, preventive measures, and surveillance of this patient group are decisive.