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Background and Purpose: Glucocorticoids are powerful anti‐inflammatory drugs, but are associated with many side‐effects. Topical application in atopic dermatitis leads to skin thinning, metabolic changes, and adrenal suppression. 5α‐Tetrahydrocorticosterone (5αTHB) is a potential selective anti‐inflammatory with reduced metabolic effects. Here, the efficacy and side‐effect profile of 5αTHB were compared with hydrocortisone in preclinical models of irritant dermatitis. Experimental Approach: Acute irritant dermatitis was invoked in ear skin of male C57BL/6 mice with a single topical application of croton oil. Inflammation was assessed as oedema via ear weight following treatment with 5αTHB and hydrocortisone. Side‐effects of 5αTHB and hydrocortisone were assessed following chronic topical steroid treatment (28 days) to non‐irritated skin. Skin thinning was quantified longitudinally by caliper measurements and summarily by qPCR for transcripts for genes involved in extracellular matrix homeostasis; systemic effects of topical steroid administration also were assessed. Clearance of 5αTHB and hydrocortisone were measured following intravenous and oral administration. Key Results: 5αTHB suppressed ear swelling in mice, with ED50 similar to hydrocortisone (23 μg vs. 13 μg). Chronic application of 5αTHB did not cause skin thinning, adrenal atrophy, weight loss, thymic involution, or raised insulin levels, all of which were observed with topical hydrocortisone. Transcripts for genes involved in collagen synthesis and stability were adversely affected by all doses of hydrocortisone, but only by the highest dose of 5αTHB (8× ED50). 5αTHB was rapidly cleared from the systemic circulation. Conclusions and Implications: Topical 5αTHB has potential to treat inflammatory skin conditions, particularly in areas of delicate skin. [ABSTRACT FROM AUTHOR]