Intralesional 5-fluorouracil (IL5-FU) has been used off-label for warts treatment; however, its use was limited by intense pain. Combination treatment can offer a robust therapeutic effect. Was to assess the therapeutic efficacy, safety and tolerability of microneedling vs its combination with 5-FU solution vs IL5-FU in the treatment of plantar warts. Ninety patients with plantar warts were divided randomly into three groups each containing 30 patients. Group A received (intralesional 5-FU), group B (microneedling) while group C (microneedling and 5-FU solution). All groups received treatment for a maximum of six sessions 2 weeks apart. Complete response was observed in 86.7% of the warts treated with 5-FU and microneedling (group C) vs to 76.7% and 70% in group A and B, respectively, with no statistically significant difference (P = .36). A significant increase in the number of sessions (P = .01) and pain score (P = .001) were found among group A compared to groups B and C. Patient's satisfaction was higher in group C (P = .05). No recurrence was reported in all groups. Microneedling can be used as alternative or adjuvant therapeutic modality for plantar warts treatment and significantly associated with less pain. Combination group was superior compared to the others.