Background: Posttraumatic stress disorder (PTSD) is a debilitating and disabling mental disorder that afflicts at least 25% of Veterans who have suffered life-threatening war zone trauma. Trauma-related nightmares and sleep disturbance are among the most treatment-resistant PTSD symptoms in Veterans. Increased responsiveness to central nervous system (CNS) norepinephrine (NE) contributes to the pathophysiology of overall PTSD and treatment-resistant nighttime symptoms. Placebo-controlled pilot studies demonstrate that the generically available CNS-active alpha-1 adrenoreceptor antagonist prazosin substantially reduces PTSD trauma nightmares and sleep disturbance and improves global clinical status (sense of well being and ability to function) in Veterans. Objective: The primary objective is to demonstrate in a large multi-site placebo-controlled trial in Veterans with war zone trauma-induced PTSD that prazosin is efficacious for PTSD trauma nightmares, sleep disturbance, and global clinical status. A secondary objective is to demonstrate prazosin effectiveness for these outcome measures during clinically meaningful long-term (26 week) maintenance treatment of PTSD. The investigators will also address prazosin efficacy and long-term effectiveness for improving total PTSD symptoms, comorbid depression, quality of life, and physical functioning. Methods: This 26 week randomized double-blind placebo-controlled study is designed to demonstrate both short term efficacy and long term effectiveness of prazosin for PTSD. The research design encompasses a shorter-term, more tightly controlled efficacy component and a longer-term, more .real world. effectiveness component. Three hundred twenty-six Veterans with war zone -related PTSD and persistent trauma nightmares will be randomized 1:1 to prazosin or placebo. Study drug will be increased using a flexible dose titration schedule based on clinical response and adverse effects to an optimum maintenance dose (1-20 mg/day). During the first 10 weeks of the study, participants will be randomized to prazosin or placebo. Previous psychotropic medications and/or psychotherapy will be maintained constant. Short term efficacy will be determined during the first 10 weeks. During the remaining 16 weeks of the 26 week trial, subjects will continue to receive stable-dose double-blind prazosin or placebo, but will have the option to receive additional psychotropic medications and/or psychotherapeutic interventions, as needed, per the judgment of the study Clinician Prescriber. It is hypothesized that prazosin will remain more clinically effective than placebo at the end of the 26-week trial, demonstrating that prazosin adds benefit over-and-above other treatments that are naturalistically administered by providers in a .real world. clinical setting. Prazosin will be judged efficacious at 10 weeks if superior to placebo on all three primary outcome measures assessing trauma nightmares, sleep disturbance, and global clinical status: the Recurrent Distressing Dreams item of the Clinician Administered PTSD Scale (CAPS), the Pittsburgh Sleep Quality Index (PSQI), and the Clinical Global Impression of Change (CGIC). Secondary outcome measures will assess prazosin effects on total PTSD symptoms, depression, physical functioning, and quality of life. Adverse effects and cardiovascular measures, including supine and standing blood pressure (BP) and heart rate (HR) will be assessed.