Background <p>Although different treatment modalities are available, the treatment of warts is still challenging with recalcitrant and recurrent lesions. Given that warts are viral in nature, acyclovir might be a viable treatment option. Intralesional acyclovir and 5-fluorouracil (5-FU) injections have been described for treating common warts and achieved a complete response in most of the patients.</p> Aim <p>The aim of this work was to assess the efficacy and safety of intralesional acyclovir versus intralesional 5-flurouracil in treatment of recalcitrant cutaneous warts.</p> Patients and methods <p>This comparative study was carried out on 60 patients diagnosed with recalcitrant cutaneous warts. The patients were categorized randomly into group I (30 patients treated with intralesional acyclovir) and group II (30 patients treated with intralesional 5-FU). Treatment was repeated every two weeks to a maximum of six sessions or until complete clearance occurred. Treatment response was assessed clinically and dermoscopically. This is the first randomized clinical trial comparing intralesional acyclovir with 5-FU for recalcitrant warts.</p> Results <p>After the end of 6 months of follow-up, complete clearance was achieved in 20 patients (66.7%) and 19 patients (63.3%) in the acyclovir and 5-FU groups, respectively. Also, complete clearance of all dermoscopic findings was observed in 66.7% of patients in the acyclovir group compared to 63.3% of patients in the 5-FU group, with no statistically significant difference between both groups (<i>p</i> &gt; 0.001). Both modalities were safe and well tolerated.</p> Conclusion <p>Intralesional acyclovir and 5-FU are safe and effective methods in treatment of recalcitrant cutaneous warts.</p>