The role of topical 5-fluorouracil (5-FU) in treating common warts is not well defined. We tried to evaluate the efficacy and adverse effects of combination cryotherapy and topical 5% 5-FU ointment in the treatment of common warts. The study was a single-centre, double-blind randomized placebo-controlled trial. In the study, 80 patients with common warts were randomized into two groups and underwent two 10-second freeze/thaw cycles of cryotherapy with liquid nitrogen once every three weeks for a maximum of five treatments. Between treatments, patients applied either topical 5% 5-FU ointment (group A) or placebo aqueous cream (group B) twice daily. The mean ± SD reduction in wart area was 58.57 ± 0.06% in group A and 65.29 ± 0.06% in group B. In total, 19 patients in group A and 24 patients in group B had wart size reduced by 75% or more (P = 0.50), while 12 patients in group A and 17 patients in group B had clearance of their warts (P = 0.245). Logistic regression with age, sex, smoking status, immune status, site, duration and number of warty lesions, history of previous treatment, and treatment group found that only a history of previous treatment and acral lesions were significant adverse predictors of improvement. There was no significant difference in the number of adverse events between the two groups, although there was a trend towards more pain and blistering associated with topical 5-FU. We concluded that topical 5-FU has no added benefit in treating common warts with cryotherapy.