This study compared the effects of buprenorphine and methadone on neonatal abstinence syndrome (NAS) in pregnant women with opioid dependence. The study was a randomized, double-blind, flexible-dosing trial involving 175 pregnant women at eight international sites. The primary outcomes were the number of neonates requiring NAS treatment, peak NAS score, total morphine needed for NAS treatment, length of hospital stay for neonates, and neonatal head circumference. Treatment was discontinued by 16 women in the methadone group (18%) and 28 women in the buprenorphine group (33%). Among the 131 participants who completed the study, those exposed to buprenorphine required significantly less morphine (mean dose, 1.1 mg vs. 10.4 mg; P<0.0091) and had a shorter hospital stay (10.0 days vs. 17.5 days, P<0.0091) and shorter NAS treatment duration (4.1 days vs. 9.9 days, P<0.003125). There were no significant differences between groups in other primary or secondary outcomes or in maternal or neonatal adverse events. The results suggest that buprenorphine can be an acceptable alternative to methadone for treating opioid dependence in pregnant women, with potential benefits for reducing the severity of NAS in neonates. However, buprenorphine may have higher discontinuation rates due to patient dissatisfaction.This study compared the effects of buprenorphine and methadone on neonatal abstinence syndrome (NAS) in pregnant women with opioid dependence. The study was a randomized, double-blind, flexible-dosing trial involving 175 pregnant women at eight international sites. The primary outcomes were the number of neonates requiring NAS treatment, peak NAS score, total morphine needed for NAS treatment, length of hospital stay for neonates, and neonatal head circumference. Treatment was discontinued by 16 women in the methadone group (18%) and 28 women in the buprenorphine group (33%). Among the 131 participants who completed the study, those exposed to buprenorphine required significantly less morphine (mean dose, 1.1 mg vs. 10.4 mg; P<0.0091) and had a shorter hospital stay (10.0 days vs. 17.5 days, P<0.0091) and shorter NAS treatment duration (4.1 days vs. 9.9 days, P<0.003125). There were no significant differences between groups in other primary or secondary outcomes or in maternal or neonatal adverse events. The results suggest that buprenorphine can be an acceptable alternative to methadone for treating opioid dependence in pregnant women, with potential benefits for reducing the severity of NAS in neonates. However, buprenorphine may have higher discontinuation rates due to patient dissatisfaction.