Besides its classical effects on salt homeostasis in renal epithelial cells, aldosterone promotes inflammation and fibrosis and modulates cell proliferation. The proinflammatory transcription factor NF-B has been implicated in cell proliferation, apoptosis, and regulation of transepithelial sodium transport. The effect of aldosterone on the NF-B pathway in principal cells of the cortical collecting duct, a major physiologic target of aldosterone, is unknown. Here, in both cultured cells and freshly isolated rat cortical collecting duct, aldosterone activated the canonical NF-B signaling pathway, leading to increased expression of several NF-B-targeted genes (IB␣, plasminogen activator inhibitor 1, monocyte chemoattractant protein 1, IL-1␤, and IL-6). Small interfering RNA-mediated knockdown of the serum and glucocorticoid-inducible kinase SGK1, a gene induced early in the response to aldosterone, but not pharmacologic inhibition of extracellular signal-regulated kinase and p38 kinase, attenuated aldosterone-induced NF-B activation. Pharmacologic antagonism or knockdown of the mineralocorticoid receptor prevented aldosterone-induced NF-B activity. In addition, activation of the glucocorticoid receptor inhibited the transactivation of NF-B by aldosterone. In agreement with these in vitro findings, spironolactone prevented NF-B-induced transcriptional activation observed in cortical collecting ducts of salt-restricted rats. In summary, aldosterone activates the canonical NF-B pathway in principal cells of the cortical collecting duct by activating the mineralocorticoid receptor and by inducing SGK1.