Objectives/Hypothesis Human papillomavirus (HPV) is a highly stable DNA virus that causes disease in human organ systems, including the larynx and oropharynx. The treatment of HPV‐associated diseases with scalpels, lasers, and other surgical instruments has the potential to release infectious particles, placing healthcare workers at risk. The objectives of this study were to create a reproducible in vivo animal model of papillomavirus infectivity and to compare the infectivity of byproducts of surgically treated mouse papillomavirus (MmuPV1) warts. Study Design Animal study. Methods Nude laboratory mice (Mus musculus) with established MmuPV1 tail warts were treated with scalpel excision, potassium titanyl phosphate (KTP) laser ablation, and coblator treatment. Uninfected nude mice were challenged with surgical byproducts, including ablated and heated tissue, and surgical smoke products. The incidence and time course of the appearance of warts was recorded. Results There was rapid transmission of virus in mice challenged with scalpel‐treated warts, with 50% penetrance of infection at day 13 and 100% at day 32. For KTP‐treated warts, there was the slower development of infection (50% by day 35) but 100% penetrance by day 52. Coblator‐treated tissue reached 50% penetrance at day 59 and a maximum of 73% penetrance. Smoke plume captured during treatment with the KTP laser and coblator was highly infectious, as was the material captured in a laser filter. Conclusions MmuPV1 remains infectious in all modes of surgically treated tissue, and the smoke plume is capable of transmitting infection. Healthcare workers should use appropriate precautions to lower their risk of infection when treating papillomavirus‐associated diseases. Level of Evidence NA Laryngoscope, 130:712–717, 2020