Remarkably, our findings reveal the high prevalence of S6 phosphorylation, a surrogate marker of mTORC1 activation, in HNSCC specimens (>70%) and, more importantly, demonstrate for the first time its relevance on clinical outcome: phosphorylation of ribosomal protein S6 on either Ser235/236 or Ser240/244 was a significant inverse predictor of lymph node metastasis, regional recurrence and distant metastasis. This evidence concerns the gene RPS6 and head and neck squamous cell carcinoma.