Topical 5-fluorouracil (5-FU) is an antineoplastic antimetabolite that inhibits DNA and RNA synthesis, thereby preventing cell replication and proliferation. This mechanism of action may allow topical 5-FU to be utilized in the treatment of human papilloma virus (HPV). We conducted a study comparing 5% 5-FU cream under tape occlusion versus tape occlusion alone in 40 patients presenting with plantar warts. Nineteen out of 20 patients (95%) randomized to 5% 5-FU with tape occlusion had complete eradication of all plantar warts within 12 weeks of treatment. The average time to cure occurred at 9 weeks of treatment. Three patients (15%) had a recurrence at the 6-month follow-up visit; accordingly, an 85% sustained cure rate was observed. It is concluded that use of topical 5% 5-fluorouracil cream for plantar warts is safe, efficacious, and accepted by the patient.