Adult and pediatric patients (n = 347) with atopic dermatitis enrolled in three multicenter, randomized, 6-week studies who had previously used steroids were analyzed to examine the null hypothesis that improvement in atopic dermatitis initiated after prior treatment with steroids eliminates any subsequent treatment differences between tacrolimus ointment and pimecrolimus cream. Of these patients, 171 were randomized to tacrolimus ointment and 176 to pimecrolimus cream. Based on improvement in the Eczema Area and Severity Index at the end of study, tacrolimus ointment was significantly more effective than pimecrolimus cream (p = 0.0002). Tacrolimus ointment was also significantly more effective than pimecrolimus cream at the end of study in all secondary end-points. Overall, the frequency of adverse events was comparable between treatment groups (24.0% for tacrolimus ointment vs. 25.6% for pimecrolimus cream). Tacrolimus ointment is more effective, with a similar safety profile, compared with pimecrolimus cream in patients with atopic dermatitis previously treated with topical corticosteroids.