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It is now well established that the urothelium does not act as a passive barrier but contributes to bladder homeostasis by releasing several signaling molecules in response to physiological and chemical stimuli. Here, we investigated the potential contribution of the hydrogen sulfide (H 2 S) pathway in regulating human urothelium function in β 3 adrenoceptor-mediated relaxation. The relaxant effect of BRL 37344 (0.1-300 µM), a selective β 3 adrenoceptor agonist, was evaluated in isolated human bladder strips in the presence or absence of the urothelium. The relaxant effect of BRL 37344 was significantly reduced by urothelium removal. The inhibition of cystathionine-γ-lyase (CSE), but not cystathionine-β-synthase (CBS), significantly reduced the BRL 37344 relaxing effect to the same extent as that given by urothelium removal, suggesting a role for CSE-derived H 2 S. β 3 adrenoceptor stimulation in the human urothelium or in T24 urothelial cells markedly increased H 2 S and cAMP levels that were reverted by a blockade of CSE and β 3 adrenoceptor antagonism. These findings demonstrate a key role for urothelium CSE-derived H 2 S in the β 3 effect on the human bladder through the modulation of cAMP levels. Therefore, the study establishes the relevance of urothelial β 3 adrenoceptors in the regulation of bladder tone, supporting the use of β 3 agonists in patients affected by an overactive bladder.