Background: There are many therapeutic modalities for plantar warts, however treating it remains challenging. Intralesional injection of 5-fluorouarcil and combined digoxin and furosemide were observed to be effective and safe, however no comparison study between them was done. Aim: Our study was conducted to evaluate the efficacy of both therapies in the treatment of plantar warts. Methods: 90 adult patients with multiple recalcitrant plantar warts were included in our study. They were randomly allocated to one of three groups; combined digoxin and furosemide, 5-fluorouarcil, or normal saline group. Fortnightly injections were done into all studied warts till complete clearance or up to 5 sessions. Warts were evaluated clinically and dermoscopically. Results: Clinical response was reported in 24 patients (80%) of the combined digoxin and furosemide group with 40% complete response and in 24 patients (80%) of the 5-fluorouarcil group with 33.3% complete response. No statistically significant difference was observed between the two groups concerning efficacy and safety. Conclusions: Intralesional injection of 5-fluorouarcil and combined digoxin and furosemide are nearly equivalent in efficacy and safety for plantar wart treatment. Dermoscopy helps to take the truthful judgment about complete clearance of warts.