Background: The pathogenesis of rosacea is incompletely understood. Signaling neuropeptides, including PACAP, a regulator of vasodilation and edema, are upregulated in rosacea skin. Here, we evaluated PACAP38-induced rosacea features and examined whether a 5-HT_1B/1D receptor agonist could reduce these features. Methods: A total of 35 patients with erythematotelangiectatic rosacea received an intravenous infusion of 10 pmol/kg/minute of PACAP38 followed by an intravenous infusion of 4 mg sumatriptan or placebo (saline) on two study days in a double-blind, randomized, placebo-controlled, and cross-over trial. Results: PACAP38 increased facial skin blood flow by 90%, dilated the superficial temporal artery by 56%, and induced prolonged flushing and facial edema. Compared with placebo, sumatriptan reduced PACAP38-induced facial skin blood flow for 50 minutes (P = 0.023), constricted the superficial temporal artery for 80 minutes (P = 0.010), and reduced duration of flushing (P = 0.001) and facial edema (P < 0.001). Conclusions: We established a clinical experimental model of rosacea features and showed that sumatriptan was able to attenuate PACAP38-induced rosacea flushing and edema. Findings support a key role of PACAP38 in rosacea flushing pathogenesis. It remains unknown whether PACAP38 inhibition can improve rosacea. Trial register: The trial was registered at ClinicalTrials.gov NCT03878784 in March 2019.