Introduction: Clinical management of verruca is a challenging issue for both dermatologists and patients. Multiple visits for treatment are usually required, and recurrence is common. Objective: to compare the efficacy of intralesional 5-FU with that of intralesional bleomycin in treatment of warts. The plantar and periungual warts were selected as an example of refractory and resistant warts. Patients and methods: Forty three patients having 52 plantar warts (group A) and 34 periungual warts (group B) were enrolled in this study. Two symmetric plantar or two symmetric periungual warts were selected for treatment in each patient. In group A, one wart was injected with 5-FU (4mg of 50mg/ml) (group A1) and the second wart was injected with bleomycin solution (1U/ml) (groupA2) randomly. Also in group B, one wart was injected with 5-FU (group B1) and the second wart was injected with bleomycin solution (1U/ml) (group B2) randomly. Patients received up to four injections at 2 weeks intervals. Clinical response was defined in terms of complete response (cured), partial and no response . The cured patients were followed at 2and 6 months after the initial injection to detect recurrences. Results: Complete response was observed in 73.1% of plantar warts and 82.4% of periungual warts treated with 5-FU compared to 73.1% of plantar warts and in 82.3% of periungual warts treated with bleomycin (P ˃.05). Thirty two patients (74.5%) found 5-FU injection more painful than bleomycin injection (P˂.05). Conclusions: Intralesional 5-FU had the same efficacy as intralesional bleomycin in treatment of plantar and periungual warts with high success rate.