ABSTRACT There is currently a dearth of FDA-approved medications developed specifically for women with alcohol use disorder (AUD). This represents a major public health concern for several reasons. First, robust sex- and gender-related differences set women at a marked disadvantage for progressing to severe AUD more quickly than men (telescoping). Second, alcohol consumption levels in women have been steadily moving towards parity with men. Third, women with AUD remain challenging to recruit into research trials, as many have caregiving commitments and/or feel stigmatized. Together these factors compound the need to develop new relapse prevention medications tailored to women, using methods that encourage women into clinical trials. Hence, a 12-week multicenter clinical trial is proposed, using a validated remote platform, which has been successful at increasing both recruitment and compliance in substance using women. Overarching aims are to examine whether 3mg/d of guanfacine extended release (GXR) Vs placebo (PBO) can reduce drinking severity in AUD women by targeting alcohol craving and emotion regulation during stress. Prior research suggests that these relapse-related processes may represent risk factors particularly pertinent to women and unique to the pharmacodynamics of guanfacine. N=70 women with AUD will be recruited at the primary site (Stony Brook) and N=60 at the secondary site (Rutgers) into a 12-week, randomized, double-blind, placebo-controlled clinical trial. Momentary reports of drinking severity, stress, craving, mood, arousal, anxiety, and emotion regulation will also be collected throughout the day and evening via three, 2-week bursts of Ecological Momentary Assessment (EMA), across the 12-week trial (weeks 1 and 2; weeks 5 and 6; and weeks 9 and 10). All data will be collected using smartphone technology. Participants will also take part in twice weekly remote visits for the entire 12 weeks to assess safety, vitals, collect urines, monitor alcohol use, and receive weekly Medical Management. It is anticipated that GXR will decrease the number of positive urines across the 12 weeks and the % number of days spent drinking (H1a, primary outcomes), as well as the mean number of drinks consumed per occasion and mean number of binge drinking sessions (H1b, secondary outcomes) compared with PBO. It is also expected that GXR Vs PBO will attenuate momentary ratings of stress-induced drinking and alcohol craving (H2a), as well as momentary ratings of stress-induced emotion dysregulation, negative mood, arousal, and anxiety (H2b) such that women taking GXR will have greater decreases in craving and use trajectories over time (H2c). The efficacy of using a remote platform will additionally be explored by ascertaining attendance, compliance and medication adherence rates. Findings will help determine the efficacy and underlying mechanisms of a potentially well-tolerated medication developed specifically for AUD women. The multi-site desi...