Background: Phosphodiesterase 3 (PDE-3) inhibition have been implicated in the neurobiologic underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to ascertain whether PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. Methods: We tested cilostazol, which inhibits PDE-3, in a randomized, double-blind, placebo-controlled, two-way crossover study involving persons with PPTH attributed to mild traumatic brain injury. The randomized participants were allocated to receive oral administration of either 200-mg cilostazol or placebo (calcium tablet) on two separate experiment days. The primary end point was the incidence of migraine-like headache during a 12-hour observation window post-ingestion. The secondary endpoint was the area under the curve (AUC) for reported headache intensity scores during the same observation window. Results: Twenty-one persons underwent randomization and completed both experiment days. The mean participants’ age was 41.4 years, and most (n = 17) were females. During the 12-hour observation window, 14 (67%) of 21 participants developed migraine-like headache post-cilostazol, in contrast to three (14%) participants after placebo (P =.003). The headache intensity scores were higher post-cilostazol than after placebo (P <.001). Conclusions: Our results provide novel evidence showing that PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. Given that PDE-3 inhibition increases intracellular cAMP levels, our findings allude to the potential therapeutic value of targeting cAMP-dependent signaling pathways in the management of PPTH. Further investigations are imperative to substantiate these insights and delineate the importance of cAMP-dependent signaling pathways in the neurobiologic mechanisms underlying PPTH. ClinicalTrials.gov Identifier: NCT05595993.