Background Perioral dermatitis (POD) is a common dermatosis without standard therapy. Objective We sought to evaluate pimecrolimus cream 1% in POD. Methods We conducted a multicenter, randomized, double-blind, parallel-group study in adult patients with POD treated twice daily with pimecrolimus cream 1% or vehicle until clearance for up to 4 weeks. Follow-up took place 4 and 8 weeks after treatment. Results Patients treated with pimecrolimus had an average POD Severity Index score of 2.6 compared with 3.5 for patients treated with vehicle. Both groups had baseline scores of 5.2. The between-group difference was 0.9 (95% confidence level 0.4, 1.4, P = .0011). Patients with history of topical corticosteroids benefited most. Pimecrolimus-treated patients reported greater improvement in quality of life. There were no group differences regarding safety. Limitations Pimecrolimus vehicle is not a true placebo. Conclusions Pimecrolimus rapidly improves clinical symptoms and quality of life of patients with POD, being most effective in corticosteroid-induced POD.