ABSTRACT The development of effective pharmacotherapies to treat alcohol use disorder (AUD) is a public health priority. Few medications are currently approved to treat AUD and those that are remain limited by modest treatment responses. Combining pharmacological interventions with evidence-based behavioral interventions may help optimize treatment outcomes. While several effective behavioral interventions for AUD have been developed, the vast majority target individual patients, despite evidence that behavioral interventions for couples with AUD outperform individual treatments for AUD. Alcohol Behavioral Couples Therapy (ABCT) is an evidence-based behavioral intervention for couples that has been shown to significantly reduce AUD severity as well as improve relationship functioning, which is an important mechanism in treatment outcome for AUD. Accumulating evidence from our group and others suggests that oxytocin is a promising candidate pharmacotherapy to further enhance ABCT, reduce AUD severity and improve relationship functioning. Previous studies demonstrate oxytocin's ability to reduce craving, alcohol consumption, symptoms of tolerance and withdrawal, and ameliorate neurobiological deficits associated with AUD. Furthermore, oxytocin has been shown to increase prosocial factors (e.g., trust, social cognition) and restore sensitivity to natural rewards (e.g., intimate relationships). To date, no studies have examined the synergistic effects of combining oxytocin with ABCT in the treatment of AUD. Thus, the primary objective of this Stage II study is to examine the effects of oxytocin versus placebo in combination with ABCT in reducing AUD severity and improving relationship functioning. We will also utilize advanced neuroimaging techniques before and after treatment to investigate the underlying pathophysiology of AUD among couples and identify prognostic indicators of treatment outcome. To accomplish this, we will (1) employ a two-arm randomized, double-blind, between-groups experimental design that will consist of 12 weeks of ABCT treatment with oxytocin or placebo; (2) use standardized, repeated dependent measures of change including alcohol biomarkers at five time points (baseline, week 6, week 12, and 3- and 6-month follow-up); (3) measure impairment in associated mental and behavioral health problems (e.g., depression); and (4) use functional magnetic resonance imaging (fMRI) to examine changes in corticolimbic connectivity. The proposed study directly addresses the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in that it aims to examine the efficacy of a novel pharmacologic agent for the treatment of AUD. The findings from this study will provide critical new information to help inform clinical practice and accelerate research on the pharmacological treatment of AUD.