The objective of the study is to prove the efficacy of the new Smartprobe system, which is based on Electrical Bioimpedance (EBI) sensing technology in the diagnosis of the head and neck squamous cell carcinoma. A prospective observational ex-vivo study was carried out analyzing 43 patients submitted to surgical procedures for head and neck squamous cell carcinoma (SCC) between May, 2019 and October, 2020. The Smartprobe system is composed by a laptop with a specific software connected to an electrode-needle to punch and analyze the EBI of ex vivo tissue. By measuring the variation of the phase (σ) and conductivity (θ), the device can distinguish healthy from pathologic tissue. The outcomes have been compared to the definitive histopathological di-agnosis as gold standard. For different tissue types, five classifiers were developed to analyze the accuracies of the methodic. The accuracy of these classifiers, on the testing set, was 74.52%, 88.37%, 76.19%, 72.81%, and 89.58% for mucosa, skin, muscle, lymph node and cartilage, respec-tively.The results of this study demonstrate that the SmartProbe technology is helpful in distin-guishing squamous cell carcinomas from healthy tissue in the mucosa, muscle, skin, and cartilage but not in the lymph nodes. This issue could be explained because of similarity of the electrical cellular characteristic between the lymphatic tissue and the hypercellularity of the SCC tissue, particularly when relatively low frequencies are used for their assessment.