Summary Background Reports of successful treatment of atopic dermatitis (AD) with mycophenolate mofetil (MMF) have thus far been limited to adults. Considering that the condition typically develops during childhood and is most active during this period, MMF would represent a valuable addition to the therapeutic armamentarium for paediatric AD. Objectives To evaluate the safety and efficacy of MMF in the treatment of severe childhood AD. Methods A retrospective analysis was performed of all children treated with MMF as systemic monotherapy for severe, recalcitrant AD between August 2003 and August 2006 at New York University Medical Center. Fourteen patients meeting these criteria were identified. Results Four patients (29%) achieved complete clearance, four (29%) had > 90% improvement (almost complete), five (35%) had 60–90% improvement and one (7%) failed to respond. Initial responses occurred within 8 weeks (mean 4 weeks), and maximal effects were attained after 8–12 weeks (mean 9 weeks) at MMF doses of 40–50 mg kg−1 daily in younger children and 30–40 mg kg−1 daily in adolescents. The medication was well tolerated in all patients, with no infectious complications or development of leucopenia, anaemia, thrombocytopenia or elevated aminotransferases. Conclusions This retrospective case series demonstrates that MMF can be a safe and effective treatment for severe, refractory AD in children. MMF represents a promising therapeutic alternative to traditional systemic immunosuppressive agents with less favourable side-effect profiles, and prospective controlled studies are warranted, further to assess its benefits in paediatric AD.