BACKGROUND: The pentaspan protein CD133 (Prominin-1) is a predictive marker and part of the signature of tumour-initiating cells (TICs) for various cancer entities. METHODS: The correlation of CD133 expression with clinical parameters was assessed in primary samples of head and neck squamous cell carcinomas (n = 98) and normal mucosas (n = 24). RESULTS: A gradual and inversely proportional correlation between CD133 expression in primary tumours and decreased overall survival was observed, along with a positive correlation with the presence of lymph node metastases. CONCLUSIONS: CD133 has the potential of being a novel clinically relevant prognostic marker for head and neck malignancies, which is possibly involved in regulation of tumourigenicity.