Purpose of review <p>Sleep disturbances in post-traumatic stress disorder (PTSD) remain a major clinical challenge. Prazosin is widely prescribed to treat PTSD-related nightmares, but its efficacy has been questioned after the largest trial was negative. This paper evaluates the complex clinical trial and real-world data on the use of prazosin in PTSD to provide guidance to clinicians.</p> Recent findings <p>The clinical trial literature for prazosin is complex and conflicting. Early small trials consistently found moderate to large effects for prazosin on nightmares, sleep quality, and overall PTSD symptoms. The largest clinical trial for prazosin in PTSD did not outperform placebo, and two large trials of prazosin and doxazosin in comorbid PTSD-alcohol use disorder did not show benefit on PTSD measures. Real-world prescribing of prazosin does not align with any interpretation of the clinical trial literature: the vast majority of dosing is far below the doses used in positive clinical trials and prazosin is frequently prescribed in comorbid PTSD-alcohol use disorder despite primarily negative trials.</p> Summary <p>Prazosin exemplifies the challenge of evidence-based prescribing in psychiatry when there is a conflicting evidence-base. Clinicians should recognize the uncertainty around prazosin’s efficacy and recognize the trade-offs in using this medication. On the one hand, low dose prescribing of prazosin is not supported by any major clinical trial and appeared ineffective in flexible-dose trials. On the other hand, if there is significant uncertainty about prazosin’s efficacy, higher doses of prazosin could subject patients to real risks for primarily non-pharmacological benefits.</p>