Background: As a living heart valve substitute with growth potential and improved durability, tissue-engineered heart valves (TEHVs) may prevent reinterventions that are currently often needed in children with congenital heart disease. We performed early health technology assessment to assess the potential cost-effectiveness of TEHVs in children requiring right ventricular outflow tract reconstruction (RVOTR). Methods: A systematic review and meta-analysis was conducted of studies reporting clinical outcome after RVOTR with existing heart valve substitutes in children (mean age ≤12 years or maximum age ≤21 years) published between January 1, 2000, and May 2, 2018. Using a patient-level simulation model, costs and effects of RVOTR with TEHVs compared with existing heart valve substitutes were assessed from a health care perspective applying a 10-year time horizon. Improvements in performance of TEHVs, divided in durability, thrombogenicity, and infection resistance, were explored to estimate quality-adjusted life year (QALY) gain, cost reduction, headroom, and budget impact associated with TEHVs. Results: Five-year freedom from reintervention after RVOTR with existing heart valve substitutes was 46.1% in patients less than or equal to 2 years of age and 81.1% in patients greater than 2 years of age. Improvements in durability had the highest impact on QALYs and costs. In the improved TEHV performance scenario (durability ≥5 years and –50% other valve-related events), QALY gain was 0.074 and cost reduction was €10,378 per patient, translating to maximum additional costs of €11,856 per TEHV compared with existing heart valve substitutes. Conclusions: This study showed that there is room for improvement in clinical outcomes in children requiring RVOTR. If TEHVs result in improved clinical outcomes, they are expected to be cost-effective compared with existing heart valve substitutes.