Background Several destructive and immunotherapeutic methods are used in treatment of plantar warts, but an effective method with no or reduced recurrence has not been found till now. Objectives To evaluate the efficacy and safety of intralesional (IL) vitamin D3 (Vit.D3) injection vs IL tuberculin purified protein derivative (PPD) injection in the treatment of plantar warts. Methods Sixty patients with plantar warts were randomized into 3 equal groups: group I treated using IL tuberculin PPD every 2 weeks, group II treated using IL Vit.D3 every 4 weeks, and group III treated with IL saline every 2 weeks till complete clearance or for a maximum of 3 sessions. The follow‐up period was 6 months. Results There was a statistically significant improvement in therapeutic groups than control with more significant improvement in group II than I. Regarding number of sessions required for complete response, there was a positive significant correlation in both groups, but more significant in group I. There was a negative correlation between the number of lesions and the response to treatment in both groups. Group II showed significantly better response to treatment in male patients. Both modalities were well tolerated, with no remarkable side effects and no recurrence in cured patients of both groups. Conclusions Both IL PPD and Vit.D3 injection are safe and effective for treatment of plantar warts even recalcitrant or multiple, with no postprocedural downtime, better results, and patient satisfaction. IL Vit.D3 injection has a superior advantage than PPD.