A 40-year-old man presented with a 10-year history of severe adult-onset AD. Despite treatment with numerous antihistamines, topical steroids, topical tacrolimus, oral and topical antibiotics, psoralen–UV-A, methotrexate, cyclosporine, and mycophenolate mofetil, he continued to have baseline severe disease with at least 2 exacerbations per year. Notable improvement only occurred with a combination of antibiotics and high-dosage oral steroids, which resulted in Cushing syndrome. At presentation, his regimen consisted of mycophenolate mofetil, topical tacrolimus, cetirizine, and montelukast sodium. A physical examination revealed erythematous, exudative, excoriated, and lichenified plaques involving 75% of his TBSA. Treatment with a prednisone taper, fluticasone propionate ointment (applied twice daily every day for 2 weeks, followed by twice daily application every other day for 2 weeks, followed by twice daily application on 2 consecutive days, followed by 5 days off treatment every week thereafter), topical tacrolimus, and doxepin hydrochloride was started. Despite intensive treatment, the patient returned 11 months later with similar lesions involving 90% of his TBSA. Rosiglitazone, a slow prednisone taper, triamcinolone acetonide, fluticasone propionate as needed, and pimecrolimus were added. Rosiglitazone maleate was started at 2 mg twice daily for 2 weeks and then increased to 4 mg twice daily. After 4 months of treatment, despite the completion of the steroid taper 4 weeks earlier, the patient improved to 75% TBSA involvement. There was resolution of acute changes with residual lichenification and mild erythema. No adverse drug effects were seen with rosiglitazone, and to date there have been no relapses of AD during 12 months of follow-up.