Head and neck squamous cell carcinomas (SCCHN) are not rare malignancies and account for 7% of all solid tumors. Prognosis of SCCHN patients strongly depends on tumor extension, site of onset, and genetics. Advanced disease (recurrent/metastatic) is associated with poor prognosis, with a median overall survival of 13 months. In these patients, immunotherapy may represent an interesting option of treatment, given the good results reached by check-point inhibitors in clinical practice. Nevertheless, only a minor number of patients with advanced disease respond to immunotherapy, and, disease progressions/hyper-progressions are common. The latter could be a very difficult issue, especially in patients having a wide and highly symptomatic head/neck mass. Given the potentiality to boost the immune response of some local modalities, such as electrochemotherapy, a possible future approach may take into account the combination of electrochemotherapy and immunotherapy to treat patients affected by SCCHN, suffering from symptomatic lesions that need rapid debulking.