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Objective: Evaluate the efficacy and tolerability of prazosin for prophylaxis of headaches following mild traumatic brain injury in active‐duty service members and military veterans. Background: Prazosin is an alpha‐1 adrenoreceptor antagonist that reduces noradrenergic signaling. An open‐label trial in which prazosin reduced headache frequency in veterans following mild traumatic brain injury provided the rationale for this pilot study. Methods: A 22‐week parallel‐group randomized controlled trial which included 48 military veterans and active‐duty service members with mild traumatic brain injury–related headaches was performed. The study design was based on International Headache Society consensus guidelines for randomized controlled trials for chronic migraine. Following a pre‐treatment baseline phase, participants with at least eight qualifying headache days per 4 weeks were randomized 2:1 to prazosin or placebo. After a 5‐week titration to a maximum possible dose of 5 mg (morning) and 20 mg (evening), participants were maintained on the achieved dose for 12 weeks. Outcome measures were evaluated in 4‐week blocks during the maintenance dose phase. The primary outcome measure was change in 4‐week frequency of qualifying headache days. Secondary outcome measures were percent participants achieving at least 50% reduction in qualifying headache days and change in Headache Impact Test‐6 scores. Results: Intent‐to‐treat analysis of randomized study participants (prazosin N = 32; placebo N = 16) demonstrated greater benefit over time in the prazosin group for all three outcome measures. In prazosin versus placebo participants, reductions from baseline to the final rating period for 4‐week headache frequency were −11.9 ± 1.0 (mean ± standard error) versus −6.7 ± 1.5, a prazosin minus placebo difference of −5.2 (−8.8, −1.6 [95% confidence interval]), p = 0.005 and for Headache Impact Test‐6 scores were −6.0 ± 1.3 versus +0.6 ± 1.8, a difference of −6.6 (−11.0, −2.2), p = 0.004. The mean predicted percent of participants at 12 weeks with ≥50% reduction in headache days/4 weeks, baseline to final rating, was 70 ± 8% for prazosin (21/30) versus 29 ± 12% for placebo (4/14), odds ratio 5.8 (1.44, 23.6), p = 0.013. The trial completion rate of 94% in the prazosin group (30/32) and 88% in the placebo group (14/16) indicated that prazosin was generally well tolerated at the administered dose regimen. Morning drowsiness/lethargy was the only adverse effect that differed significantly between groups, affecting 69% of the prazosin group (22/32) versus 19% of the placebo group (3/16), p = 0.002. Conclusions: This pilot study provides a clinically meaningful efficacy signal for prazosin prophylaxis of posttraumatic headaches. A larger randomized controlled trial is needed to confirm and extend these promising results. [ABSTRACT FROM AUTHOR]