Objectives
To investigate whether a radiomic MRI feature‐based prediction model can differentiate oropharyngeal squamous cell carcinoma (SCC) according to the human papillomavirus (HPV) status.

Study Design
Retrospective cohort study.

Methods
Pretreatment MRI data from 62 consecutive patients with oropharyngeal SCC were retrospectively reviewed, and chronologically allocated to training (n = 43) and test sets (n = 19). Enhancing tumors were semi‐automatically segmented on each slice of the postcontrast T1WI to span the entire tumor volume, after registration of T2WI to postcontrast T1WI; 170 radiomic features were extracted from the entire tumor volume. Relevant features were selected and radiomics models were trained using least absolute shrinkage and selection operator (LASSO) logistic regression model with 10‐fold cross‐validation, after subsampling of training sets using synthetic minority over‐sampling technique to mitigate data imbalance. The selected features, weighted by their respective coefficients, were combined linearly to yield a radiomics score. The diagnostic performance of the radiomic score was evaluated using the area under the receiver operating characteristic curve (AUC).

Results
Six radiomic features, which revealed strong association with HPV status of oropharyngeal SCC, were selected using LASSO. The radiomics model yielded excellent performance on the training set (AUC, 0.982 [95% CI, 0.942–1.000]) and moderate performance on the test set (AUC, 0.744 [95% CI, 0.496–0.991]) for differentiating oropharyngeal SCC according to HPV status.

Conclusions
Radiomics‐based MRI phenotyping differentiates oropharyngeal SCC according to HPV status, and thus, is a potential imaging biomarker.