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Severe combined immunodeficiency (SCID) is a condition that often results in severe infections and death at young age. Early detection shortly after birth, followed by treatment before infections occur, largely increases the chances of survival. As the incidence of SCID is low, assessing cost-effectiveness of adding screening for SCID to the newborn screening program is relevant for decision making. Lifetime costs and effects of newborn screening for SCID were compared to a situation without screening in the Netherlands in a decision analysis model. Model parameters were based on literature and expert opinions. Sensitivity analyses were performed. Due to earlier detection, the number of deaths due to SCID per 100,000 children was assessed to decrease from 0.57 to 0.23 and a number of 11.7 quality adjusted life-years (QALYs) gained was expected. Total yearly healthcare costs, including costs of screening, diagnostics, and treatment, were €390,800 higher in a situation with screening compared to a situation without screening, resulting in a cost-utility ratio of €33,400 per QALY gained.Conclusion: Newborn screening for SCID might be cost-effective. However, there is still a lot of uncertainty around the cost-effectiveness estimate. Pilot screening projects are warranted to obtain more accurate estimates for the European situation. What is Known: • Severe combined immunodeficiency (SCID) is a condition that often results in severe infections and death at a young age. • As the incidence of SCID is low, assessing cost-effectiveness of adding screening for SCID to the newborn screening program is needed. What is New: • Newborn screening for SCID is expected to reduce mortality from 0.57 to 0.23 per 100,000 children at additional healthcare costs of €390,800. The cost-utility ratio is €33,400 per QALY gained. • Due to large uncertainty around cost-effectiveness estimates, pilot screening projects are warranted for Europe. [ABSTRACT FROM AUTHOR]