This study aimed to compare the efficacy and safety of oral methotrexate (MTX) and oral mini-pulse (OMP) dexamethasone alone and in combination in the treatment of vitiligo. A total of 42 patients with vitiligo were included in the study. The patients were treated for three months and randomly assigned into three groups including 14 patients each: group A received oral MTX, group B received OMP dexamethasone, and group C received a combination of both. Follow-up was performed using digital photographs, Vitiligo European Task Force score, and dermoscopy. Disease extension significantly decreased in group C compared with that in groups A (P < .001) and B (P < .05). The frequency of intralesional pigmentation significantly increased (P < .05) in groups A and C and decreased (P < .05) in group B posttreatment noted using a dermoscope. Moreover, the frequency of micro-Koebner's phenomenon and starburst pattern significantly decreased (P < .05) in groups B and C and that of tapioca sago in group C only posttreatment.