BACKGROUND AND PURPOSE: The incidence of Oropharyngeal Squampus Cell Carcinoma (OPSCC) cases is increasing especially in the Western countries due to the spreading of human papilloma virus (HPV) infection. Radiological investigations, MRI in particular, are used in the daily clinical practice to stage OPSCC. The aim of this study was to investigate the association of quantitative MR imaging features including diffusion-weighted imaging and human papillomavirus status in oropharyngeal squamous cell carcinoma. MATERIALS AND METHODS: We retrospectively analyzed 59 patients with untreated histologically proved T2–T4 oropharyngeal squamous cell carcinoma. Human papillomavirus status was determined by viral DNA detection on tissue samples. MR imaging protocol included T2-weighted, contrast-enhanced T1-weighted (volumetric interpolated brain examination), and DWI sequences. Parametric maps of apparent diffusion coefficient were obtained from DWI sequences. Texture analysis was performed on T2 and volumetric-interpolated brain examination sequences and on ADC maps. Differences in quantitative MR imaging features between tumors positive and negative for human papillomavirus and among subgroups of patients stratified by smoking status were tested using the nonparametric Mann-Whitney U test; the false discovery rate was controlled using the Benjamini-Hochberg correction; and a predictive model for human papillomavirus status was built using multivariable logistic regression. RESULTS: Twenty-eight patients had human papillomavirus-positive oropharyngeal squamous cell carcinoma, while 31 patients had human papillomavirus-negative oropharyngeal squamous cell carcinoma. Tumors positive for human papillomavirus had a significantly lower mean ADC compared with those negative for it (median, 850.87 versus median, 1033.68; P < .001). Texture features had a lower discriminatory power for human papillomavirus status. Skewness on volumetric interpolated brain examination sequences was significantly higher in the subgroup of patients positive for human papillomavirus and smokers (P = .003). A predictive model based on smoking status and mean ADC yielded a sensitivity of 83.3% and specificity 92.6% in classifying human papillomavirus status. CONCLUSIONS: ADC is significantly lower in oropharyngeal squamous cell carcinoma positive for human papillomavirus compared with oropharyngeal squamous cell carcinoma negative for it. ADC and smoking status allowed noninvasive prediction of human papillomavirus status with a good accuracy. These results should be validated and further investigated on larger prospective studies.