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Introduction: Topical corticosteroids (TCS), used to treat atopic dermatitis (AD), have been associated with type 2 diabetes and osteoporosis in epidemiological studies, possibly explained by systemic absorption. Objectives: We examined whether intensive daily whole‐body TCS treatment over 2 weeks followed by twice weekly application for 4 weeks could elicit insulin resistance and increase bone resorption in adults with AD. Methods: A randomized parallel‐group double‐blind double‐dummy non‐corticosteroid‐based active comparator study design was completed in Copenhagen, Denmark. Thirty‐six non‐obese, non‐diabetic adults with moderate‐to‐severe AD were randomized to whole‐body treatment with betamethasone 17‐valerate 0.1% plus a vehicle once daily or tacrolimus 0.1% twice daily after washout. Insulin sensitivity assessed by the hyperinsulinemic‐euglycemic clamp combined with tracer infusions and biomarkers of bone formation (P1NP) and resorption (CTX) were evaluated at baseline, after 2 weeks of daily treatment and after further 4 weeks of twice‐weekly maintenance treatment. Results: AD severity improved with both treatments and systemic inflammation was reduced. After 2 weeks, we observed similar increase in peripheral insulin sensitivity with use of betamethasone (n = 18) and tacrolimus (n = 18). Bone resorption biomarker, CTX, was unchanged, while bone formation marker, P1NP, decreased after betamethasone treatment after both 2 and 6 weeks but remained unchanged in the tacrolimus arm. Conclusions: Whole‐body treatment with TCS leads to systemic exposure but appears not to compromise glucose metabolism during short‐term use, which may be a result of reduced systemic inflammatory activity. The negative impact on bone formation could be regarded an adverse effect of TCS. [ABSTRACT FROM AUTHOR]