Background Plantar warts are common skin lesions caused by the human papilloma virus. It is characterized by the presence of a horny ring of hyperkeratosis surrounding the wart, making its elimination a therapeutic challenge. Several destructive agents are available for treatment with variable success. Intralesional vitamin D3 has been reported as a successful treatment of warts. Intralesional zinc sulfate has been found to be another successful therapeutic modality for wart elimination. Objective To compare the efficacy and safety of intralesional vit. D3 versus zinc sulfate in treatment of plantar warts. Patients and methods Forty patients were included in the study. Patients were randomly assigned to either vit. D3 group or zinc group. In vit. D3 group, patients received intralesional injection of 0.3 ml vitamin D3 (100,000 IU (2.5 mg/ml)), while zinc group patients received intralesional 2% zinc sulfate. Assessment of treatment efficacy and safety was carried out by clinical examination and comparative photographic evaluation before each session and up to 3 months after the last session. Results Eighty percent of vit. D3 treated patients and 70% of zinc sulfate patients showed complete response. Conclusions Intralesional vit. D3 and zinc sulfate appear to be effective treatment modalities for plantar warts.