We recently demonstrated that blockade of the mineralocorticoid receptor (MR) effectively ameliorated GC-induced skin atrophy in healthy human skin explants and epidermal MR knockout mice. However, whether MR blockade improves the therapeutic index of glucocorticoids (GCs) in skin pathology was not investigated. We assessed the effects of GCs, MR antagonists (MRA) or both, in SDS-treated human skin explants. All treatments restored SDS-augmented epidermal thickness but only GC plus MRA restored the expression of COL1A1. However, MRA alone or in combination with GCs may exert a dual role in regulating inflammatory cytokines. Thus, although combined treatment may be beneficial to improve irritative skin, extensive in vivo testing is required to establish whether the anti-inflammatory effects of GCs are maintained in the presence of MRA.