OBJECTIVE To determine the effects of in utero exposure to methadone or buprenorphine on infant neurobehavior. METHODS Three sites from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial participated in this substudy. METHODS Medical Centers that provided comprehensive maternal care to opioid-dependent pregnant women in Baltimore, MD, Providence, RI and Vienna, Austria. METHODS Thirty-nine full-term infants. METHODS The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS) was administered to a subgroup of infants on postpartum days 3, 5, 7, 10, 14-15 and 28-30. RESULTS While neurobehavior improved for both medication conditions over time, infants exposed in utero to buprenorphine exhibited fewer stress-abstinence signs (P < 0.001), were less excitable (P < 0.001) and less over-aroused (P < 0.01), exhibited less hypertonia (P < 0.007), had better self-regulation (P < 0.04) and required less handling (P < 0.001) to maintain a quiet alert state relative to in utero methadone-exposed infants. Infants who were older when they began morphine treatment for withdrawal had higher self-regulation scores (P < 0.01), and demonstrated the least amount of excitability (P < 0.02) and hypertonia (P < 0.02) on average. Quality of movement was correlated negatively with peak NAS score (P < 0.01), number of days treated with morphine for NAS (P < 0.01) and total amount of morphine received (P < 0.03). Excitability scores were related positively to total morphine dose (P < 0.03). CONCLUSIONS While neurobehavior improves during the first month of postnatal life for in utero agonist medication-exposed neonates, buprenorphine exposure results in superior neurobehavioral scores and less severe withdrawal than does methadone exposure.