PROJECT SUMMARY Neonatal Opioid Withdrawal Syndrome (NOWS) is a major public health problem in the USA. About 100,000 American infants were exposed to opioids in 2017 and 25,000 of these infants were diagnosed with NOWS. Opioid-exposed infants have poorer outcomes compared to similar non-exposed infants including longer and more complicated initial hospital stays, higher likelihood of involvement in the child welfare system, higher rates of hospital readmission and emergency department visits, and lower use of recommended preventive services. One group of infants at particularly high risk for adverse outcomes are infants who receive pharmacological therapy to treat signs of withdrawal. Importantly, the care, treatment, and outcomes of these infants vary widely between birth hospitals and US states. Such variation suggests that the optimal pharmacological treatment for NOWS remains unknown, potentially exposing these infants to unnecessary or ineffective management. The NOWS Treatment Trial will assess the optimal pharmacological treatment for NOWS through a multicenter, comparative effectiveness trial comparing three commonly used medications. This application describes the CHOP/Penn Neonatal Clinical Trials Network, our outstanding team of investigators with vast clinical trial experience, our unparalleled research environment, and our large and diverse patient population which together ensure that we are ideally suited to participate in the design and execution of the NOWS Treatment Trial. We will contribute expertise in clinical trial methodology, substance abuse, and neonatal follow-up, providing rigorous scientific input into design and implementation of the multicenter NOWS Treatment Trial. We will then execute all aspects of the trial to the highest standard, including robust participant recruitment, rigorous adherence to all aspects of the study protocol, and neurodevelopmental follow-up to two years with minimal attrition.