Background: Following a traumatic event, 40-80% of the patients with acute stress disorder (ASD) will develop post-traumatic stress disorder (PTSD), 67% at 6 months. Alpha1-blockers are effective in treating some symptoms of PTSD but their usefulness in acute stress situations remains unclear. We hypothesized that reducing noradrenergic hyperactivity with an alpha1-blocker during the acute phase after a traumatic event could prevent the transition to PTSD in patients with ASD. Objective: To investigate the efficacy and safety of a 1-month course of alpha1-blocker (prazosin) to prevent the transition to PTSD in patients with ASD at 6 months. Method: In a monocentric open-label prospective pilot study, 15 patients with ASD were included within 3-7 days of exposure to a traumatic event. After enrolment, they received prazosin LP at home at bedtime at 2.5 mg/day for 7 days and then 5 mg/day for 21 days. Incidence of PTSD was assessed at 6 months using the Clinician Administrated PTSD Scale (CAPS). Results: At 6 months, 22% of patients who completed the study (2/9) met the diagnostic criteria for PTSD. This rate was significantly lower than that observed in previous studies (67%; p = .047). The treatment was well tolerated and there were no serious adverse events. Conclusions: These preliminary findings indicating the safety of prazosin and suggesting its potential to prevent the development of PTSD in ASD require to be replicated in large-scale randomized placebo-controlled studies. Trial registration: The study was pre-registered on a public database (www.clinicalTrials.gov identifier: NCT03045016).