Aim of the study <p>To evaluate the efficacy and safety of microneedling combined with tacrolimus 0.03% ointment versus microneedling combined with phenytoin 2% cream in the treatment of non-segmental facial vitiligo.</p> Materials and methods <p>This was a prospective single-blinded randomized clinical trial conducted on a total of 40 patients with non-segmental facial vitiligo, who were distributed into two groups (each of 20 patients); group I (<i>n</i> = 20) were treated with microneedling combined with tacrolimus 0.03% ointment and group II (<i>n</i> = 20) treated with microneedling combined with phenytoin 2% cream. The approach was conducted for another time every 14 days for all cases for over a period of 6 months, then the cases were followed up for three months following the termination of the treatment sessions.</p> Results <p>There were no statistically significant differences recorded between both groups in regard to all demographic data and disease characteristics (<i>P</i> &gt; 0.05). As regards to clinical improvement, microneedling combined with tacrolimus 0.03% ointment was associated with a superior improvement compared to microneedling combined with phenytoin 2% cream, nevertheless, this improvement was not statistically significant. Also, microneedling combined with tacrolimus was associated with a higher patient satisfaction compared to microneedling combined with phenytoin 2% cream, however, this improvement was not associated with statistical significance.</p> Conclusion <p>Our results provide additional evidence for the potential positive role of phenytoin as a therapeutic option in patients with non segmental vitiligo. However, tacrolimus 0.03% ointment combined with microneedling was associated with a better response than phenytoin 2% cream combined with microneedling.</p>