Objective: To determine the effect a novel formulation of fluocinonide cream on skin barrier function in subjects with atopic dermatitis., Design: The authors performed an open-label, investigator-blinded, side-by-side, controlled trial examining skin barrier function before and after a two-week course of a class I, super-potent topical steroid., Setting: Outpatient university-based dermatology clinic in Portland, OR., Subjects: Twenty-five subjects aged 12 or older with a diagnosis of moderate, severe, or very severe AD were recruited for this study., Intervention: Fluocinonide 0.1% cream, a novel formulation of a class I super-potent topical steroid was applied to all affected areas, except a control site, once daily for two weeks or until clear. The control target site was treated with the vehicle once daily., Main Outcome Measure(s): The study's primary outcome was change in skin barrier function as measured by basal transepidermal water loss (TEWL) in acute lesional skin from baseline as measured at two weeks., Results: TEWL readings significantly decreased (reflecting improved barrier function) in both the active and control target sites. The active target site decreased 14.35+/-16 mg/cm2 per hour; 95 percent confidence interval, P<0.001. The control target site decreased 8.75+/-11.80 mg/cm2 per hour in 25 subjects; 95 percent confidence interval, P<0.001. Skin electrical capacitance also improved significantly, reflecting improved stratum corneum hydration with therapy. Pruritus, clinical severity, and quality of life scores all showed significant improvement by the end of the study., Conclusion: The authors have shown that short-term treatment with a novel formulation of 0.1% fluocinonide led to significantly improved barrier function as measured by basal TEWL in subjects with active moderate to severe AD. These data suggest short-term treatment with AD with a super-potent corticosteroid improves skin barrier function.