Although topical corticosteroids are the mainstay of treatment of atopic dermatitis (AD), these medications may lose efficacy over time, a phenomenon known as tachyphylaxis. However, the underlying mechanism for tachyphylaxis may be due to lack of treatment adherence rather than loss of efficacy of topical corticosteroids. In this study, we aimed to determine if AD patients who were previously unsuccessfully treated with topical corticosteroids would respond to desoximetasone spray 0.25% under conditions designed to promote good adherence over a 7-day period. At baseline, patients were randomized to receive either twice-daily telephone calls to discuss treatment adherence (intervention group) or no telephone calls (control group) during the study period. The patients improved rapidly. In most patients, treatment-resistant AD is most likely due to poor adherence to treatment rather than loss of drug responsiveness.