Background: Human papillomavirus (HPV) is a causative agent of oropharyngeal squamous cell carcinoma (HPVOPC). There are multiple different HPV genotypes based on variations in the nucleotide sequence of the L1 capsid, with HPV16 being most common in HPVOPC (85%). HPV genotypes can be further classified into phylogenic clades, including alpha-9 (A9) and alpha-7 (A7). HPVOPC is associated with a more favorable prognosis than HPV-negative disease, but the impact of specific HPV genotype and phylogenic clade on patient outcomes is not well understood and has profound implications for de-escalation studies in HPVOPC. Methods: A retrospective cohort study was conducted at a large multicenter health system. Patients diagnosed with non-metastatic HPVOPC or unknown primary from 2012-2021 and treated with curative intent were included. Low-risk HPV types (6, 11, etc) and local recurrences were excluded. HPV molecular typing was prospectively performed according to institutional protocol. Cox regressions were used to measure the effect of HPV genotype (16 versus non-16) on overall survival (OS) and event-free survival (EFS). Gender, smoking status, alcohol use, ECOG performance status, T stage, N stage, and subsite (oropharynx versus known primary) were covariates. A secondary survival analysis according to high-risk HPV clade (A9 versus A7) was also performed. Results: The total cohort included 520 patients, the majority of whom were HPV16 (86.9%, n = 452), A9 clade (97.1%, n = 505), oropharynx primary (94.8%, n = 493), male (86.9%, n = 452), white (72.5%, n = 377), non-Hispanic (74.2%, n = 386), non-active smokers (88.3%, n = 459), ECOG 0 (75.6%, n = 393), and N2 stage (65.2%, n = 339). The most common non-16 HPV genotypes were 18 (n = 7), 33 (n = 21), and 35 (n = 29). HPV genotype was not associated with OS (HR = 1.64, 95% CI 0.85-3.16, p= 0.14) or EFS (HR = 1.15, 95% CI 0.64-2.07, p= 0.65). A7 clade was associated with a worse OS compared to A9 in the univariate analysis (HR = 3.43, 95% CI 1.07-10.97, p= 0.04), but not in the multivariate analysis (HR = 1.67, 95% CI 0.45-6.17, p = 0.44). Finally, HPV clade was not associated with EFS (HR = 1.38, 95% CI 0.34-5.60, p= 0.66). Conclusions: While HPV genotype was not associated with survival differences in patients with HPVOPC, HPV A7 clade only predicted worse OS in univariate analysis. Although the total cohort size was large, this analysis was limited by small numbers of subjects with non-16 HPV genotypes and non-A9 clade, which is reflective of the predominance of HPV16 in HPVOPC. Thus, a pooled multicenter collaboration is needed to further address this question. Moreover, future studies should investigate whether outcomes may be related to intratypic HPV16 variants that affect oncoprotein function and/or immunogenicity. Detection of a subgroup of HPVOPC with possible inferior outcomes has important implications for studying treatment de-escalation in HPVOPC.