Background The concept of head and neck cancers (HNSCC) having unique molecular signatures is well accepted but relating this to clinical presentation and disease behaviour is essential for patient benefit. Currently the clinical significance of HNSCC molecular subtypes is uncertain therefore personalisation of HNSCC treatment is not yet possible. Methods We performed meta-analysis on 8 microarray studies and identified six significantly up- (PLAU, FN1, CDCA5) and down-regulated (CRNN, CLEC3B and DUOX1) genes which were subsequently quantified by RT-qPCR in 100 HNSCC patient margin and core tumour samples. Results Retrospective correlation with sociodemographic and clinicopathological patient details identified two subgroups of opposing molecular signature (+q6 and -q6) that correlated to two recognised high-risk HNSCC populations in the UK. The +q6 group were older, male, and excessive alcohol users whilst the –q6 group were younger, female, paan-chewers and predominantly Bangladeshi. Additionally, all patients with tumour recurrence were in the latter subgroup. Conclusions We provide the first evidence linking distinct molecular signatures in HNSCC with clinical presentations. Prospective trials are required to determine the correlation between these distinct genotypes and disease progression or treatment response. This is an important step towards the ultimate goal of improving outcomes by utilising personalised molecular-signature-guided treatments for HNSCC patients.