Acute pulmonary edema (APE) is one of the fatal outcomes after exposure to high levels of hydrogen sulfide (H2S), available evidence suggest that dexamethasone (DXM), a potent anti-inflammatory agent, has been widely used or proposed as a therapeutic approach for H2S-induced APE in clinical practice, however, the underlying mechanism remains poorly understood. Ample evidence suggest that epithelial Na(+) channel, especially for the subunit α-epithelial Na(+) channel (α-ENaC) plays a critical role in alveolar fluid clearance. Therefore, the present study is undertaken to investigate the effects of DXM on α-ENaC following H2S exposure. The Sprague Dawley rats were exposed to H2S to establish APE model, in parallel, A549 cells were treated with NaHS to establish cell model. In vivo study, we found that DXM significantly attenuated H2S-induced lung histopathological changes and alveolar fluid clearance decrement, however, these preventive effects of DXM can be obviously counteracted by the mifepristone (MIF), the glucocorticoid receptor (GR) blocker. Moreover, DXM markedly attenuated H2S-mediated α-ENaC down-regulation, and similarly, the process can be partially retarded by MIF. Furthermore, DXM obviously prevented H2S-mediated ERK1/2 activation both in vitro and in vivo study. These results, taken together, suggested that DXM exerted protective effects on H2S-induced APE, and α-ENaC might be a potential therapeutic target for APE induced by H2S.