We have reported that TNF, a pro-inflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na⁺ channel (ENaC) by ~70% in alveolar epithelial cells. Because dexamethasone has been shown to upregulate ENaC mRNA expression, and is well-known to downregulate pro-inflammatory genes, we tested if it could alleviate the effect of TNF on ENaC expression and activity. In co-treatment with TNF, we found that dexamethasone reversed the inhibitory effect of TNF and upregulated , and ENaC mRNA expression. When the cells were pre-treated for 24 h with TNF prior to co-treatment, dexamethasone was still able to increase ENaC mRNA expression to 1.8-fold above control values. However, in these conditions, and ENaC mRNA expression was reduced to 47% and 14% respectively. The potential role of TNF and dexamethasone on ENaC promoter activity was tested in A549 alveolar epithelial cells. TNF decreased Luc expression by ~25% in these cells, indicating that the strong diminution of ENaC mRNA must be related to post-transcriptional events. Dexamethasone raised Luc expression by 5-fold in the cells and augmented promoter activity by 2.77-fold in co-treatment with TNF. In addition to its effect on ENaC gene expression, dexamethasone was able to maintain amiloride-sensitive current as well as the liquid clearance abilities of TNF-treated cells within the normal range. All these results suggest that dexamethasone alleviates the downregulation of ENaC expression and activity in TNF-treated alveolar epithelial cells.