We present here a study of gas-phase reactivity of cobalt sulfide cluster anions ComSn- with molecular oxygen. Nascent ComSn- clusters were prepared via a laser ablation source and reacted with oxygen in a fast flow reactor under thermal collision conditions. We chose O-18(2) in place of O-16(2) to avoid mass degeneration with sulfur, and a time-of-flight (TOF) mass spectrometer was used to detect the cluster distributions in the absence and presence of the reactant. It was found that oxygen-sulfur exchange occurs in the reactions for those with specific compositions (CoS)(n)(-) and (CoS)(n)S- (n = 2-5) according to a consistent pathway, "ComSn- + O-18(2) -> (ComSn-1O-)-O-18 + (SO)-O-18". Typically, for Co2S2- + O-18(2)" we have calculated the reaction coordinates by employing the density functional theory (DFT), where both the oxygen-sulfur exchange and SO molecule release are thermodynamically and kinetically favorable. It is noteworthy that the reaction with molecular oxygen (triplet ground state) needs to overcome a spin excitation as well as a large O-O activation energy. This study sheds light on the activation of molecular oxygen by cobalt sulfides on one hand and also provides insight into the regeneration mechanism of cobalt oxides from the counterpart sulfides in the presence of oxygen gas on the other hand.