To investigate the role of the altered activation of the immune system in the prognosis of patients affected by laryngeal squamous cell carcinoma (LSCC). We analyzed 56 patients with advanced LSCC divided into two groups according to their prognosis: the first group relapsed within 24 months after treatment, the second group had no evidence of disease at 2 years. The presence of stromal tumor infiltrating lymphocytes (TILs) at the tumor-host border was investigated. In 43 patients we evaluated the expression of 395 genes related to immune system activation through a next generation sequencing panel. Priority-LASSO models and clustering analyses were integrated with multivariate Cox proportional hazard modeling to identify independent genes associated with relapse and estimate hazard ratios in relation to gene expression and TILs. TILs and the expression of genes related with immune system activation (FCGR1A, IFNA17, FCRLA, NCR3, KREMEN1, CD14, CD3G, CD19, CD20 and CD79A) were significantly associated with prognostic factors or disease specific survival. In patients with lymph node metastases and advanced T stage (pT4), the expression of other genes was altered. Low TILs count was highly associated with relapse within 2 years (p < 0.001). Low TILs and altered expression of specific genes associated with tumor-immune systems interactions emerged as independent risk factors, associated to poor prognosis and relapse within 2 years in advanced LSCC. Evaluation of patients' immune profile could be useful for prognosis and future therapeutic approaches towards personalized therapy.