Background; Vitiligo is a common skin disease, characterized by the selective loss of basal cell layer melanocytes, which in turn leads to loss of pigment in the affected areas of the skin. Aim of work; to evaluate the efficacy of microneedling with topical methotrexate versus microneedling with topical 5-fluorouracil in management of vitiligo patients. Subjects & methods; this randomized trial involved 30 patients aged ≥ 18 years with stable vitiligo. Three patches in each patient were treated by 6 sessions as follows: The 1st patch (A) was received microneedling followed by methotrexate (MTX) 25 mg\ml solution application. The 2nd patch (B) was received microneedling followed by 5-flurouracil (5-FU) 50mg\ml solution application. The 3rd patch (C) was received microneedling followed by saline application. Result; our study revealed significantly better outcomes in patches treated by microneedling and MTX or 5-FU solutions compared to microneedling with saline. VASI scores improved more in the MTX and 5-fluorouracil groups (28.5% and 31.03%) than in the saline group (15.8%). After 3 months follow up, 60% of patients in the MTX and 5-fluorouracil groups achieved good to excellent repigmentation, while 40% in the saline group had poor results. Conclusion; our study demonstrated that microneedling combined with either topical methotrexate or 5-fluorouracil is a safe and effective modality for vitiligo treatment. Both combination therapies showed superior efficacy compared to microneedling alone, with high patient satisfaction rates and manageable side effects.