Background: We evaluated the utility of HNSCC LN R2* relaxation times to infer the oxygenation status of LN non-invasively at baseline and when breathing air and 100% oxygen to predict chemoradiotherapeutic locoregional response at 2 years. Hypoxia within LNs has been associated with poorer outcomes following CRT. Deoxyhaemoglobin decreases MRI transverse relaxation time (T2*) (lengthening inverse, R2*). Methods: A total of 54 patients underwent 1.5T-MRI before CRT. Conventional MR sequences were supplemented with T2* sequences breathing both air and 100% oxygen; pathological nodes identified in consensus were volumetrically contoured to T2* parametric maps. Results: Patients followed-up with for >2 years were categorised by multidisciplinary consensus into post-therapy complete local response (CR; n = 32/54) and local nodal disease relapse (RD; n = 22/54). Our data demonstrated, by R2*, that nodes that sustained post-therapy CR are significantly more hypoxic compared with relapsing nodes and paradoxically demonstrate a significant increase in hypoxia on 100% oxygen. Pre-treatment LN short axis diameter, various qualitative descriptors of malignancy, and quantitative DWI were not useful in discriminating successful response to CRT. Conclusions: This study demonstrates that a significant differential response to 100% oxygen and higher baseline R2* LN measurements could be exploited in risk stratification prior to CRT, and future work could be directed towards understanding the contrast mechanisms of R2* imaging, underpinning the observed differences in the context of hypoxia.