Background: Viral warts are caused by human papillomavirus (HPV), are difficult to treat with conventional modalities, and are cosmetically disfiguring; hence, immunomodulators are being used. The viral origin of warts suggests the antiviral drug acyclovir as a potential therapeutic option. The current study compares the effect of intralesional acyclovir (nucleoside analogue) and intralesional purified protein derivative (PPD) (immunotherapy) in treating various viral warts.Methodology: Prospective observational comparative study was conducted to determine the efficacy of acyclovir, and PPD administered via the intralesional route in patients with viral warts. The study population was categorized into two groups. One group received intralesional acyclovir, and the other received intralesional PPD. Patients were followed-up with for three months. Outcomes considered in our study were recovery (complete, partial, and no recovery) and side effects like pain, burning sensation, and desquamation. Statistical analysis was carried out by coguide software.Results: In our study total of 40 participants, 20 in each group were included. 25 and 15 were of age <30, and ≥ 30, respectively, while 20 were males, and 20 females. Our study reported 60%, and 30% of complete recovery with intralesional acyclovir treatment and intralesional PPD treatment, respectively, in the twelfth week. However, p-value > 0.05 represented no significance between groups. 90% in the acyclovir-treated group presented with pain, and 100% presented with burning sensation, while in the case of PPD-treated group, 60% presented no side effects and the rest 40% showed pain.Conclusions: Intralesional acyclovir is more effective in treating viral warts than PPD. The focus is to be laid on anticipated side effects.