OBJECTIVES To assess cost-effectiveness ratio of MS/MS screening for PKU and MCADD in Spanish communities. METHODS A decision tree model was developed. One branch represented the scenario where MS/MS was implemented for PKU and MCADD screening, while another branch represented the scenario without MS/MS technology (no screening for MCADD). Analysis was performed from the Health System perspective and the time horizon was newborn's lifetime. Main model parameters were obtained from a Spanish newborn screening program, scientific literature, and expert's recommendations. The selected effectiveness measure was years of life gained (LYG) and discount rate was 3%. Stochastic and multivariate sensitivity analysis was performed, and acceptability curves were calculated RESULTS Case of decentralized screening programs along Communities, and about 90-100 thousand births per year (/Y); the incremental cost-effectiveness ratio (ICER) is €5936/LYG and CI [€5866/LYG; €5986/LYG]. However, when births number is around 5,000/Y, ICER is €30,554 /LYG and CI [€30,236/LYG; €30,877/LYG]. For a willingness to pay around €30,000/LYG, probabilities of right decision of each scenario are 100% and 43.28% respectively CONCLUSIONS The introduction of MS/MS neonatal screening for PKU and MCADD offers favourable cost-effectiveness ratio. Cost-effectiveness ratio becomes better with growing number of annual screenings with MS/MS, remaining more or less constant on 30-40 thousand infants/Y.The findings of this report support MS/MS introduction for PKU and MCADD screening in Spanish Communities, when alive newborns number is superior to 5000/Y.