###### Abstract  
(1) Background The incidence of oral cavity lesions related to human papillomavirus (HPV) is 3%. There are no reliable data in the literature on recurrence rates of HPV-related oral cavity lesions. The only data available concern gynecological infections, which have a recurrence rate of ~30%. Recurrence may be due to a failure to completely eradicate the lesion, persistence of the viral infection, or persistence of an immune-compromised state. Therefore, the study aimed to ascertain the most effective therapeutic strategy to achieve complete eradication of the virus and avoid a possible recurrence of lesions, based upon the long-term behavior of the virus with the type of treatment. (2) Methods: Systematic searches of the Cochrane Library, EMBASE, Pubmed, Web of Science, clinicaltrials.gov, and SCOPUS were performed. Restrictions were placed on the date of publication and language. Only English or Italian language articles published between Jan 1990 and Dec 2019 were included in the meta-analysis. The following keywords and/or corresponding medical subject heading terms were used: _\"oral papillomavirus lesions\"_ and _\"oral HPV lesions\"_ or _\"treatment\"_, _\"therapy\"_, _\"therapeutics_,\" and _\"management\"_. (3) Results: Upon systematic literature review of all analyzed HPV-lesion treatment techniques, 36 studies on laser and cold scalpel radiations were selected. These studies document an excellent success rate from excisional treatments using both laser and cold scalpel and report low recurrence rates with both techniques, respectively 5.98% and 4.07%. (4) Conclusions: The meta-analysis revealed that additional studies with greater sample sizes are needed for these two treatment methods. It would also be appropriate to carry out case-controlled studies, preferably RCTs, to determine the best treatment for eradicating HPV-related lesions. oral HPV-related lesions; human papillomavirus; meta-analysis; treatment strategies; oral HPV treatment 11 April 2021 30 April 2021 30 April 2021 their cutaneous counterpart. The labial mucosa and palate are the most common intraoral sites of VV infection. The lesions are pink to white, sessile, usually less than 1 cm in size, and display exophytic fronds [5]. SP is a common lesion and the most frequent benign oral epithelial entity in both children and adults. The palate and tongue are most affected, but any site may be involved. Clinically, SP is characterized by exophytic \"finger-like\" projections. SPs are usually pedunculated, with colors ranging from white to pink/red. The lesions are rarely larger than 5 mm in dimension and usually solitary [6]. CA is uncommon in the oral cavity. Adults in their 30s and 40s are most affected by CA. Clinically, CA may present as a solitary lesion or in multiples, some of which may fuse to form larger growths. The lesions may be pedunculated but are more often sessile with cauliflower-like or a moruloid surface texture and pink to white coloration. The tongue and upper lip are the most common intraoral locations for CA [7]. MEH lesions are associated with a genetic susceptibility due to human leukocyte antigen subtype HLA-DR4. MEH is most often reported in particular populations, such as Navajo and Alaskan Eskimo children, indigenous children in the Americas, and AIDS patients. MEH is characterized by multiple lesions of varying sizes and affects various sites. Two clinical presentations are described in the literature: the more common papulonodular variant and a papillomavirus one. The papulonodular lesions tend to occur on the buccal and labial mucosa and are mucosal-colored and flat. Those papilomatous presentations occur more often on the masticatory mucosa of the tongue and gingiva, with white and pebbly surfaces. Lesions of both variants range in size from 1 mm to 1 cm, often with coalescence [8]. Occurrences on the palate are rare, and the floor of the mouth is spared.