Background: Substance use in pregnancy is associated with severe maternal and fetal morbidities and substantial economic costs. However, few studies have evaluated the cost-effectiveness of substance use treatment programs in pregnant women. The purpose of this study was to evaluate the economic impact of a behavioral intervention that integrated motivational enhancement therapy with cognitive behavioral therapy (MET-CBT) for treatment of substance use in pregnancy, in comparison with brief advice. Methods: We conducted an economic evaluation alongside a clinical trial by collecting data on resource utilization and performing a cost minimization analysis as MET-CBT and brief advice had similar effects on clinical outcomes (e.g., alcohol and drug use and birth outcomes). Costs were estimated from the health care system's perspective and included intervention costs, hospital facility costs, physician fees, and costs of psychotropic medications from the date of intake assessment until 3-month postpartum. We compared effects of MET-CBT on costs with those of brief advice using Wilcoxon rank sum tests. Results: Although the integrated MET-CBT therapy had higher intervention cost than brief advice (median = $ 1297/participant versus $ 303/participant, p < 0.01), costs of care during the prenatal period, delivery, and postpartum period, as well as for psychotropic medications, were comparable between the two groups (all p values = 0.55). There was no statistically significant difference in overall cost of care (median total cost = $ 26,993/participant for MET-CBT versus $ 27,831/participant for brief advice, p = 0.90). Conclusions: The MET-CBT therapy and brief advice resulted in similar clinical outcomes and overall medical costs. Further research incorporating non-medical costs, targeting women with more severe substance use disorders, and evaluating the impact of MET-CBT on participants' quality of life will provide additional insights.