The objective of this study was to compare the efficacy and safety of tacrolimus ointment and pimecrolimus cream in adults with moderate atopic dermatitis (AD). A randomized, investigator-blinded, 6-week, multicenter study enrolled patients (> or =16 years) with mild to very severe AD. Patients with moderate AD at baseline were analyzed. At study completion, tacrolimus ointment-treated patients had significantly greater improvement in Eczema Area Severity Index score compared with pimecrolimus cream-treated patients (59% versus. 43% reduction, respectively; P=.01). Significantly more tacrolimus ointment-treated patients than pimecrolimus cream-treated patients improved by 1 or more grades on the Investigators' Global Atopic Dermatitis Assessment (P<.02). A total of 5 pimecrolimus cream-treated patients discontinued the study early due to lack of efficacy compared with no tacrolimus ointment-treated patients (P=.02). Overall, reported adverse events occurred at a similar frequency for both treatment groups. Tacrolimus ointment is more effective than pimecrolimus cream in the management of adults with moderate AD.