Oxygen (O2) sensing by the carotid body is critical for maintaining cardiorespiratory homeostasis during hypoxia. Hydrogen sulfide (H2S) signaling is implicated in carotid body activation by low O2. Here, we show that persulfidation of olfactory receptor 78 (Olfr78) by H2S is an integral component of carotid body activation by hypoxia. Hypoxia and H2S increased persulfidation in carotid body glomus cells and persulfidated cysteine240in Olfr78 protein in heterologous system.Olfr78mutants manifest impaired carotid body sensory nerve, glomus cell, and breathing responses to H2S and hypoxia. Glomus cells are positive for GOlf,adenylate cyclase 3 (Adcy3) and cyclic nucleotide–gated channel alpha 2 (Cnga2), key molecules of odorant receptor signaling.Adcy3orCnga2mutants exhibited impaired carotid body and glomus cell responses to H2S and breathing responses to hypoxia. These results suggest that H2S through redox modification of Olfr78 participates in carotid body activation by hypoxia to regulate breathing.