Hydrogen sulfide (HS) is an endogenous gasotransmitter with anti-inflammatory actions that also reduces itching. To test whether a combination of an antihistamine with a HS donor has improved antipruritic efficacy, bifunctional molecules with antihistamine and HS-releasing pharmacophores were synthesized and tested and . HS release from the hybrid molecules was evaluated with the methylene blue and lead acetate methods, and H1-blocking activity was assessed by determining tissue factor expression inhibition. All new compounds released HS in a dose-dependent manner and retained histamine blocking activity. Two compounds with the highest potency were evaluated for their antipruritic as well as sedative action; they proved to possess higher efficacy in inhibiting histamine-induced pruritus and decreased sedative effects compared to the parent compounds (hydroxyzine and cetirizine), suggesting that they exhibit superior antipruritic action and limited side effects that likely arise from the HS-releasing moiety.