The wars in Iraq and Afghanistan are associated with high rates of post-traumatic stress disorder (PTSD) and comorbid alcohol use disorders. The pharmacotherapy of these comorbid conditions has received relatively little study. The current study compared the serotonin uptake inhibitor, paroxetine, to the norepinephrine uptake inhibitor, desipramine. It also evaluated the adjunctive efficacy of the Food and Drug Administration (FDA)-approved alcoholism pharmacotherapy, naltrexone, relative to placebo. Four groups of predominately male veterans (n=88) meeting current diagnostic criteria for both alcohol dependence (AD) and PTSD were randomly assigned under double-blind conditions to one of four groups: paroxetine+naltrexone; paroxetine+placebo; desipramine+naltrexone; desipramine+placebo. Main outcome measures included standardized scales that assessed symptoms of PTSD and alcohol consumption. Paroxetine did not show statistical superiority 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 it conferred no advantage on drinking use outcomes. Although the serotonin uptake inhibitors are the only FDA-approved medications for the treatment of PTSD, the current study suggests that norepinephrine uptake inhibitors may present clinical advantages when treating male veterans with PTSD and AD. However, naltrexone did not show evidence of efficacy in this population. This study was registered with ClinicalTrials.gov, registration number NCT00338962 and URL: http://clinicaltrials.gov/ct2/show/NCT00338962?term=desipramine+AND+alcohol+dependence+AND+depression&recr=Closed&rank=1.