Atopic dermatitis (AD) is a chronic inflammatory and pruritic skin disorder marked by alternating periods of relapse and remission. This multicenter, randomized, active- and vehicle-controlled, investigator-blinded study compared the efficacy and safety of clobetasol propionate lotion to clobetasol propionate cream formulation and lotion vehicle in the treatment of moderate to severe AD. A total of 229 subjects applied treatment twice-daily for 2 weeks. Clobetasol propionate lotion was significantly more effective than its lotion vehicle at 2 weeks and comparable to the cream formulation. Clinical success after a 2-week, treatment-free follow-up period was greater in the clobetasol propionate lotion group than in the cream group. Clobetasol propionate lotion is effective, safe, well tolerated and offers a better remission profile in the treatment of moderate to severe AD as compared to clobetasol propionate emollient cream.