Background: Plantar warts exhibit an annual incidence of 14% of all types of warts.Incidence varies with age, sex, race, and health status. 5-FU and podophyllin resin had been reported to be effective in treating warts. Aim of study: To assess the therapeutic efficacy of topical 5- FU cream and 25% podophyllin solution in tincture of benzoin in treatment of plantar warts. Methods: An open therapeutic trial conducted in the Department of Dermatology and Venereology in Al – Yarmouk Teaching Hospital, Baghdad, Iraq during the period from 1st of June to 1st of December 2021.It involved 52 patients wih age above 15 year diagnosed with plantar warts for more than six months’ duration and not on treatment in the last two months. Patients with diabetes mellitus, underwent renal transplantation, with circulatory problems , on steroid treatment, and pregnant and lactating women were excluded from the study.Each patient was treated with 5-FU cream and 25% podophyllin solution alternatively .The patients were followed up after three, six, and 9 weeks , with clinical assessment of response and side effects on each visit. Results: There were 35(67.3%) males and 17 (32.7%) females with male to female ratio of 2.05 :1.The patients’ age was ranging from 16 – 52 and 27 ( 51.9%) of them were employees. There were statistical significant reductions in mean size of warts after three, six, and nine weeks compared to baseline size. The assessment after nine weeks showed response in 118(90.8%) lesions,from those, 98(75.4%) lesions showed complete response (score 2) , while only 12 (9.2%) of plantar lesions were refractory to treatment by the end of treatment period (score 0) Hyperpigmentation was noticed at application sites of nine lesions (6.92%) in three (5.76%) patients. There was no scar formation at the application sites. None of the patients experienced any systemic side effect. All cured lesions (score 2) didn’t show any recurrence of warts after six weeks follow up period. Conclusion: Combination of topical 5-FU cream and 25% podophyllin solution in alternative day regimen is an effective, tolerable and safe modality of treatment of plantar warts with little local and no systemic side effects.