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RATIONALE AND OBJECTIVES The present study used diffusion-weighted imaging (DWI) to elucidate possible associations with tumor-infiltrating lymphocytes (TIL), tumor-stroma ratio and vimentin expression in head and neck squamous cell cancer (HNSCC). MATERIALS AND METHODS 30 patients with primary HNSCC of different localizations were involved in the study. DWI was obtained on a 3 T scanner. Apparent diffusion coefficients (ADC) images were analyzed with a whole lesion measurement using a histogram approach. TIL- and vimentin-expression was calculated on biopsy samples before any form of treatment. RESULTS Tumor-stroma ratio correlated with ADC kurtosis (r = 0.46, p = 0.01) and ADC skewness (r = 0.42, p = 0.02). Several ADC parameters were significantly different between stroma rich und tumor rich tumors. ADC entropy correlated significantly with the expression of TIL within the tumor compartment (r = 0.44, p = 0.01). No associations were identified between ADC parameters and vimentin expression. CONCLUSION ADC skewness and kurtosis histogram parameters can reflect tumor compartments in HNSCC. ADC entropy was associated with TIL of the tumor compartment but not with those of the stroma compartment, which emphasizes the ability of ADC histogram parameters to reflect distinctive differences of tumors.