Prevention of the flares is a main goal in the long-term treatment of atopic dermatitis (AD). Therefore we investigated the efficacy of a water-in-oil emollient, containing licochalcone A, omega-6-fatty acids, ceramide 3 and glycerol, for prevention of the flares in adults with mild to moderately severe AD, treated with topical steroids, that led to clearing of the inflammatory lesions and had been discontinued prior to inclusion. The study was a 12-week, double-blind, randomized, vehicle-controlled, left-right comparison test with the number of relapses, defined as re-occurrence of erythema for at least 3 consecutive days, considered the primary outcome. Compared with the vehicle, the active formulation significantly reduced the number of relapses and maintained the barrier homeostasis of the respective arm. To the best of knowledge, this is the first study to show prevention of the AD flares by the use of stand-alone emollient treatment, based on comparison with the corresponding vehicle while excluding concomitant/rescue medications.