Background: The prognostic significance of p16/HPV discordance in oropharyngeal squamous cell carcinoma (OPSCC) remains incompletely characterized, particularly in Asian populations. We evaluated the prevalence and prognostic significance of p16/HPV discordance using the nationwide Korean Oropharyngeal Cancer (K-OPC) cohort.Methods: We retrospectively analyzed patients with OPSCC treated at 24 institutions in Korea between 2013 and 2022. Patients with available results for both p16 immunohistochemistry and HPV testing were classified into four subtypes: HPV-negative/p16-negative, HPV-negative/p16-positive, HPV-positive/p16-negative, and HPV-positive/p16-positive. Overall survival (OS) and disease-free survival (DFS) were compared using Kaplan-Meier analysis. Multivariable Cox regression for DFS was adjusted for age, sex, smoking status, alcohol consumption, primary tumor subsite, and tumor stage.Findings: Among 1,522 patients, 316 (20·8%) were HPV-negative/p16-negative, 193 (12·7%) were HPV-negative/p16-positive, 23 (1·5%) were HPV-positive/p16-negative, and 990 (65·0%) were HPV-positive/p16-positive, yielding an overall discordance rate of 14·2%. In multivariable analysis, the HPV-negative/p16-positive and HPV-positive/p16-positive groups had significantly better DFS than the HPV-negative/p16-negative group, whereas the HPV-positive/p16-negative group showed no significant difference from the HPV-negative/p16-negative group. In adjusted pairwise comparisons, DFS did not differ significantly according to HPV status among tumors with the same p16 status, whereas p16-positive tumors had significantly better DFS than p16-negative tumors within both HPV-negative and HPV-positive groups.Interpretation: In a nationwide Korean cohort, p16/HPV discordance occurred in 14·2% of OPSCC and was predominantly HPV-negative/p16-positive. Prognosis in discordant tumors tracked with p16 status rather than HPV status, independently of stage and other clinical covariates.