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One hundred five consecutive patients with primary oropharyngeal and oral cavity head and neck squamous cell carcinoma underwent MR imaging with anatomic and DWI sequences. The collected tumor voxels from the contoured ROIs provided histograms from which position, dispersion, and form parameters were computed. Histogram data were correlated with histopathology, p16-immunohistochemistry, and polymerase chain reaction for human papillomavirus DNA. Diffusion phenotypes of human papillomavirus–positive and human papillomavirus–negative head and neck squamous cell carcinomas showed significant differences, which reflect their distinct degree of tumor heterogeneity.