Posttraumatic stress disorder (PTSD) is an anxiety disorder experienced by combat veterans. Nighttime symptoms are often unrelieved by selective serotonin reuptake inhibitor therapy, and increased use of prazosin or quetiapine for treatment is seen. The purpose of this study was to determine the short- and long-term effectiveness and safety of prazosin versus quetiapine for treating nighttime symptoms in veteran PTSD patients. This is a historical prospective cohort study using retrospective chart review. Three hundred twenty-four patients with a diagnosis of PTSD, based on International Classification of Diseases, Ninth Revision coding, who were initially prescribed prazosin or quetiapine for nighttime symptoms were screened for inclusion. Short-term effectiveness was determined by documentation of symptomatic improvement within 6 months, and long-term effectiveness if patients continued therapy to study end date. Safety was assessed by comparing incidence of adverse drug effects causing discontinuation of either study drug. This study included 237 patients: 62 received prazosin, and 175 received quetiapine. Short-term effectiveness was similar for prazosin (61.3%) and quetiapine (61.7%; P = 0.54). However, patients prescribed prazosin were significantly more likely to continue their therapy to study end date compared with quetiapine (48.4% vs 24%; P < 0.001; odds ratio, 3.0; 95% confidence interval, 1.62-5.45), thus achieving long-term effectiveness. Alternatively, patients in the quetiapine group were more likely to discontinue therapy because of adverse effects compared with the prazosin group (34.9% vs 17.7%; P = 0.008). Because of similar rate of short-term effectiveness, superior long-term effectiveness, and lower incidence of events leading to discontinuation, compared with quetiapine, prazosin should be used first-line for treating nighttime PTSD symptoms in a veteran population.