BACKGROUND: The lifetime burden of morbidity in patients with isolated congenital ventricular septal defect (VSD) is not completely described. METHODS AND RESULTS: In a population-based cohort study in Denmark using nationwide medical registries, we included 8006 patients diagnosed with a congenital VSD before 2018 along with 79 568 randomly selected controls from the general Danish population matched by birth year and sex. Concomitant congenital cardiac malformations and chromosomal abnormalities were excluded. Cox proportional hazard regression, Fine and Gray competing risk regression, and Kaplan-Meier survival function were used to estimate burden of morbidity, compared with matched controls. Median follow-up was 23 years (interquartile range, 11– 37 years). The hazard ratio (HR) of heart failure was high in both patients with unrepaired and surgically closed VSD when compared with their corresponding matched controls (5.4 [95% CI, 4.6– 6.3] and 30.5 [95% CI, 21.8– 42.7], respectively). Truncated analyses with time from birth until 1 year after VSD diagnosis (unrepaired) or surgery (surgically closed) censored revealed reduced but persisting late hazard of heart failure. Similarly, the late hazard of arrhythmias and pulmonary arterial hypertension was high irrespective of defect closure. The HR of endocarditis was 28.0 (95% CI, 19.2– 40.9) in patients with unrepaired defect and 82.7 (95% CI, 37.5–183.2) in patients with surgically closed defect. The increased HR diminished after VSD surgery. In general, the incidence of morbidity among patients with unrepaired VSD accelerated after the age of 40 years. CONCLUSIONS: Patients with isolated congenital VSD carry a substantial burden of cardiovascular morbidity throughout life, irrespective of defect closure.