Background: The most common subtype of chronic vulvar pain is provoked vestibulodynia. The entry of the vagina is the site of acute and recurrent pain in this highly prevalent and debilitating condition, which is characterized by pressure application or attempted vaginal penetration. The aim of this study was to determine the effectiveness of topical spermidine in patients with vestibulodynia. Methods: Topical gels containing spermidine in hyaluronate complexes Ubi1 and Ubi2 endowed with differentiated release ratio and viscosity were applied at 3 doses/week during 4-weeks, then at 2 doses/week during the next 4-weeks in two groups of patients. Pain relief was measured by visual analogic score (VAS) and dyspareunia score expressed as percent improvement from baseline to posttreatment. Results: Group 1 treated with Ubi1 provided improvement in pain (46%) and dyspareunia (27%). However, the treatment in Group 2 resulted in a superior amelioration: VAS of pain (76%) and dyspareunia (50%) as Ubi2 gel provided higher dose and viscosity along with improved local application. Conclusions: Our results demonstrated that preparation 2 resulted in greater reduction in symptoms as compared to preparation 1 as measured by the VAS and Marinoff scale. These early, yet outstanding clinical outcomes in vestibulodynia through to the stimulation of tissue mechanosensor and their relevant downstream effects are reviewed hereafter.