Head and neck cancer is the sixth leading cancer by incidence worldwide [
1] and comprises many different pathological entities. The diagnosis is often characterized by multifocal development and presentation at an advanced stage. [
2] The age at diagnosis usually ranges between 50 and 70 years of age and men are significantly more likely to develop the disease than women (up to a 4:1 proportion, depending on geographical localization) [
3]. Currently, two major carcinogenic pathways leading to head and neck squamous cell carcinomas are recognized: the first is associated with risk factors like smoking and abusive alcohol consumption while the second is associated with human papillomavirus (HPV) infection [
4,
5]. Over the past decade, several epidemiologic studies reported a 36.5% increase in the incidence of head and neck squamous cell carcinomas (HNSCC), particularly in high-income countries and among men < 60 years [
4,
6‐
8]. Available data indicates that these changes specifically involve oropharyngeal cancers [
9,
10]. Although tobacco consumption has decreased, the incidence of HPV-positive oropharyngeal cancers has increased [
11], indicating that HPV infection is the underlying cause for the overall increase in HNSCC incidence [
12‐
14]. Patients showing oral HPV infection are 53 times more likely to develop HNSCC [
15]. Presently, HPV is present in approximately 35% of HNSCC and most HPV-positive cases emerge in lingual and palatine tonsils [
16]. The presence of HPV DNA in tumour cells defines a specific pathologic entity within HNSCC with specific epidemiology, molecular characteristics, and biological behaviour [
17]. HPV interferes with key signaling pathways to promote carcinogenesis via its viral oncoproteins E6 and E7, which lead to the inactivation of tumour protein 53 (p53) and the retinoblastoma protein (pRB), respectively [
18]. HPV is a group of small, double-stranded DNA viruses that infect the epidermis and keratinizing mucosae. More than 100 HPV types have been identified [
19,
20]. Presently, 40 different HPV types are known to infect mucosal epithelia and are categorized into low-risk and high-risk HPV types according to their epidemiologic association with cervical cancer [
21]. In HNSCC, the majority of HPV types belong to this group including HPV16, HPV18, HPV39 and HPV45 [
22]. HPV16 is by far, the most detected type, accounting for 90% of all HPV-positive HNSCC cases [
23], a significantly greater proportion than in cervical cancer where it accounts for little over 50% of cases [
24]. Sequencing of the HPV genome also revealed intra-type variants with genetic differences ranging between 0.5 and 1% [
25,
26]. HPV variants arise mainly from nucleotide substitutions in some restricted positions in the genome coding region or in the noncoding region [
27,
28]. The prevalence of variants for each HPV type varies significantly in different geographical areas [
27]. Regarding HPV16, whole-genome analysis allowed the characterization of five distinct phylogenetic clusters named according to their original geographical distribution: European (E), Asian (As), Asian-American (AA), African 1 (Af1) and African 2 (Af2) [
29‐
31]. Subsequently, a new branch, North American 1 (NA1) was identified [
32,
33]. Currently, emerging epidemiological, etiological, and molecular data suggest that intra-type HPV variants are biologically distinct and may be associated with different risk of cervical cancer progression [
28]. I
n vitro studies using 3D organotypic epithelial cell cultures showed that HPV16
E6 variants differ in their ability to abolish keratinocyte differentiation and to induce p53 degradation [
34‐
36]. Those experimental results are corroborated by clinical studies on cervical cancer. The T350G (L83V) HPV16 variant is the most frequently found among invasive cervical cancers [
21,
37] and has been linked to a higher oncogenic potential than the prototype [
38], possibly by facilitating persistent viral infection, a critical factor for cancer development [
39‐
41]. Despite the growing number of studies concerning HPV16 variants on cervical cancer, there are currently very few reports describing their distribution in HNSCC and nothing is established about their impact on the development, treatment response and impact on disease outcome. Nonetheless, HPV16 variants may also play an important role in head and neck carcinogenesis and studying their impact is needed due to the rising incidence of HPV-positive HNSCC [
18,
23,
25,
42]. The purpose of this work is to systematically review the distribution of HPV16 variants in HNSCC and to assess the available knowledge concerning their potential contribution for HNSCC pathologic heterogeneity in published studies.