The prognosis of patients with recurrent or metastatic of the head and neck squamous-cell carcinoma (HNSCC) refractory to platinum-based chemotherapy is severe and, consequently, the identification of therapeutic options for this category of patients is a priority. Nivolumab, an anti- programmed cell death protein 1 (anti-PD-1) monoclonal antibody, has been approved for the treatment of recurrent or metastatic HNSCC after platinum-based therapy progressing. We present the early experience of two academic center including diagnostic, clinical, biological, therapeutic and outcomes characteristics of head and neck cancer (HNC) patients treated with Nivolumab. The purpose of the study is to identify certain peculiarities and to report them compared to the data from the literature in order to generate some hypotheses that coud constitute criteria for the selection of cases with maximum benefit to immunotherapy. Analyzing the data obtained from 18 patients treated in Emergency County Hospital Craiova, "Saint Nectarie" Oncological Hospital Craiova and Euroclinic Oncological Center Iasi January 2020 and March 2023 it could be hypothesized that lower nadir values of neutrophil to lymphocyte ratio (<3.5) and the adition of intensive regimens of chemotherapy and radiotherapy could justify a favorable response in terms of progression free survival (PFS) during immunotherapy with Nivolumab. To our knowledge, the study included the first two cases of second primary malignancy (SPM) in the head neck region treated with Nivolumab. The reported data support a possible benefit of the sequential administration of radiotherapy, immunotherapy for SPM cases. Higher positive dynamic of neutrophil to lymphocyt ratio (NLR) could be associated with worst outcome during immunotherapy. All study observations including the role of infections and antibiotic treatment as well as the possible biomarker value of NLR variation during immunotherapy should be investigated in multicenter clinical trials.