Objective To evaluate the long-term costs and health effects of the Swedish newborn screening program for classic phenylketonuria (PKU) alone and in combination with congenital hypothyroidism compared with no screening. Study design A decision-analytic model was developed to estimate and compare the long-term (80 years) costs and health effects of newborn screening for PKU and congenital hypothyroidism. Data were obtained from the liter-ature and translated to Swedish conditions. A societal perspective was taken, including costs falling on health care providers, municipal care and services, as well as production loss due to morbidity. Results Screening 100 000 newborns for PKU resulted in 73 gained quality-adjusted life-years (QALYs) compared with no screening. When adding congenital hypothyroidism, the number of gained QALYs was 232 compared with PKU alone, adding up to a total of 305 QALYs gained. Corresponding cost estimates were $80.8, $70.3, and $10.05 million USD for no screening, PKU screening, and PKU plus congenital hypothyroidism screening, respectively, indicating that screening for PKU plus congenital hypothyroidism was more effective and less costly compared with the other strategies. The majority of cost savings with PKU plus congenital hypothyroidism screening was due to reductions in productivity losses and municipal care and services costs. Conclusion The Swedish newborn screening program for PKU and congenital hypothyroidism saves substantial costs for society while generating additional QALYs, emphasizing the importance of public investments in early diagnosis and treatment. (J Pediatr 2023;256:38-43).