Background: To assess safety, toxicity and efficacy of neo-adjuvant nivolumab ± ipilimumab administration to (salvage) surgery for squamous cell carcinoma of the head and neck (HNSCC). Methods: Patients with (recurrent) T3-4N0-3M0 HNSCC, WHO 0-1, HPV+ and HPV-, treated at the Netherlands Cancer Institute. Phase IB consists of ARM A (n = 6, 3+3 design): nivolumab 240mg flat dose (week 1&3) and ARM B (n = 6, 3+3 design): nivolumab (week 1&3) + ipilimumab 1 mg/kg (week 1 only), neo-adjuvant to surgery (week 5) with/without adjuvant (C)RT. The efficacy of neo-adjuvant nivolumab w/wo ipilimumab in terms of pathological response and imaging (FDG-PET, MRI) will be studied in an expansion phase-II cohort (n = 20). Results: Report of Phase-I. Phase I, ARM A: Six patients with a T3-4N0-2b HNSCC of the oral cavity (n = 3) or oropharynx (n = 3) were included (5/6 patients underwent salvage surgery). All patients were treated as scheduled without surgical delay (surgery in week 5) or unexpected wound healing problems. Two patients experienced CTCAE grade 3 toxicity (1 pericarditis and 1 colitis) starting 38 and 70 days after immunotherapy, respectively, and were treated with prednisone ( 1mg/kg). In ARM B, so far, 4 patients with a T3-4N0-2c HNSCC of the oral cavity (n = 3) and supraglottis (n = 1) underwent surgery without delay. One of 4 patients underwent salvage surgery. One patient experienced CTCAE grade 3 colitis and thyroiditis, 18 days after immunotherapy, successfully treated with prednisone (1mg/kg) and 2x 5 mg/kg Infliximab after prednisone. Patients 5 and 6 of ARM B are scheduled for surgery within the coming weeks. Phase II will be open for accrual in March 2018. Conclusions: Nivolumab (240 mg flat dose, week 1&3) can be safely administered neoadjuvant to major (salvage) surgery in advanced (recurrent) HNSCC. Patients 5 and 6 of ARM B are scheduled for surgery within the coming weeks. Phase II will be open for accrual in March 2018. Clinical trial information: NCT03003637