Project Abstract Alcohol Use Disorder (AUD) is a chronic relapsing illness in which alcohol withdrawal symptoms (AW) are associated with greater treatment failure risk and higher rates of relapse and alcohol intake. Efficacy of current approved medications in AUD are modest, and none have been shown to be efficacious in those with AW. Thus, there is great need to develop and evaluate treatments to address specific prognostic indicators of high relapse and treatment failure to reduce the associated burden of AUD. Based on this previous clinical research, we hypothesized that in AUD patients with AW (AUD+AW), PR (16 mg/day) compared to PBO will significantly improve alcohol use outcomes, craving and also reduce associated anxiety and depression symptoms and improve physical health (SBP and liver enzymes) functioning and patient-related outcomes during the course of the trial and with enduring effects during over a 3 month follow up period, thereby validating AW as a prognostic indicator both of Prazosin efficacy and in AUD treatment outcome. A 12-week Phase II, single site, randomized clinical trial of Prazosin (PR: 16 mg/day, t.i.d dosing) is proposed in 150 treatment seeking men and women with AUD+ AW (3 or more symptoms) to address the following specific aims: Aim #1: To evaluate the effects of PR vs PBO on the primary alcohol use outcome of percent of subjects with no heavy drinking day (PSNHDD) and secondary drinking outcomes of %heavy drinking day (HDD%), any drinking day (DD%) and average drinks/day (AvgD) in AUD+AW patients. Aim #2: To assess the effects of PR vs PBO on other secondary stress-related outcomes of alcohol craving, depression and anxiety symptoms during the trial. Aim #3: To assess enduring short-term treatment effects of PR versus PBO on primary and other secondary outcomes at 1- and 3- month post-treatment follow-up time points. Exploratory Aim 1: To assess the effects of PR vs PBO treatment during the trial and at follow up on secondary physical health (SBP/DBP and liver enzymes) and patient-reported functioning outcomes. Exploratory Aim 2: To explore whether pre-treatment patient characteristics (gender, adversity/trauma history and lifetime PTSD) influence Prazosin effects on primary and secondary alcohol use and related outcomes. Prazosin is a commonly prescribed medication that most clinicians feel comfortable using. If successful, findings will provide important efficacy data on Prazosin’s role in AUD+AW treatment and in related secondary psychological and physical health outcomes. It will further validate AW at outpatient treatment entry as a prognostic indicator for AUD treatment and for Prazosin use among AUD+AW subgroup of patients. It will also support development of the precision medicine goal of providing specific treatment options for AUD patients with AW and stress-related pathophysiology to improve their AUD treatment outcomes.