Prior to the advent of immune checkpoint inhibitors targeting PD-1/PD-L1 axis no drug demonstrated to improve survival or quality of life in the second-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC). Nivolumab appear to have a clear clinical benefit for R/M-HNSCC, based on improved survival, good toxicity profile, reduction in symptoms and improvement in overall quality of life. This benefit seems to be greater for PD-L1 positive patients and independent of previous treatment, even being observed among heavily pre-treated patients. However, even in responding tumors acquired resistance to nivolumab usually occurred, limiting the drug’s activity. We report a case of unexpected prolonged stable disease in second-line treatment with nivolumab after a rapid progression disease under first-line chemotherapy in biomarker-positive R/M-HNSCC.