Comorbidity between posttraumatic stress disorder (PTSD) and substance use disorder (SUD) is common. As a result, the development of integrated treatments addressing both PTSD and SUD are needed. Although there are effective pharmacotherapies for the treatment of PTSD and SUD, there are no proven medications that will treat both conditions. We have conducted two clinical trials testing the safety and efficacy of medication treatments for comorbid PTSD and alcohol dependence (AD). In a 12-week clinical trial enrolling 254 patients with AD and comorbid psychiatric disorders, we compared four treatment conditions: (1) disulfiram and placebo, (2) naltrexone alone, (3) placebo alone, and (4) disulfiram and naltrexone. Patients with PTSD (n = 93) had fewer heavy drinking days and more consecutive days of abstinence when treated with naltrexone, disulfiram, or combination, as compared to placebo. This study demonstrated the efficacy of both disulfiram and naltrexone for the treatment of AD in individuals with PTSD. In the second 12-week study, a total of 88 predominantly male veterans with current diagnosis of AD and PTSD were randomly assigned one of four groups: paroxetine plus naltrexone; paroxetine plus placebo; desipramine plus naltrexone; desipramine plus placebo. Paroxetine was equivalent to desipramine for the treatment of PTSD symptoms. However, desipramine was superior to paroxetine with respect to study retention and alcohol use outcomes. Naltrexone reduced alcohol craving relative to placebo, but did not improve drinking behavior. This study suggests that norepinephrine uptake inhibitors may have efficacy for the treatment of comborbid PTSD and AD.