Objective To investigate the role of diffusion-weighted imaging (DWI) in predicting and monitoring chemoradiotherapy response in head and neck squamous cell carcinoma (HNSCC). Methods Diffusion-weighted imaging was performed pre-treatment ( n  = 50), intra-treatment ( n  = 41) and post-treatment ( n  = 20). Apparent diffusion coefficient (ADC) values were correlated with locoregional failure (LF). Results Locoregional failure occurred in 20/50 (40%) patients. A significant correlation was found between LF and post-treatment ADC ( p  = 0.02) but not pre- or intra-treatment ADC. Serial change in ADC was even more significant ( p  = 0.00001), using a fall in ADC early (pre- to intra-treatment) or late (intra- to post-treatment) to indicate LF, achieved 100% specificity, 80% sensitivity and 90% accuracy. Conclusions Single ADC measurements pre- or intra-treatment did not predict response, but ADC post-treatment was a marker for LF. Serial change in ADC was an even stronger marker, when using an early or late treatment fall in ADC to identify LF.