Concomitant radiotherapy with cetuximab, an anti-EGFR mAb, is a common treatment for locally advanced head and neck squamous carcinoma (HNSCC). CTLA-4+ regulatory T cells (Treg) dampen cellular immunity and are linked to worse clinical outcomes. An anti–CTLA-4 mAb, ipilimumab, was added to cetuximab-radiotherapy in this phase I study. To develop the recommended phase II dose (RP2D) of ipilimumab, which was given at week 5 for four every-3-week doses to fixed, standard cetuximab radiation therapy, a 3+3 design was utilized.Stage III to IVb, high-risk [human papillomavirus–negative (HPV-) or intermediate-risk HPV-positive) HNSCC were eligible. Grade 4 adverse event (AE) is defined as any type of dose-limiting toxicity (DLT), with the exception of in-field radiation dermatitis or immune-related (ir) AE necessitating systemic steroids for >2 weeks. Immune correlatives were evaluated by collecting tumor and regular blood samples at baseline and on a periodic basis. From July 2013 to May 2016, 18 patients enrolled. Grade 3 dermatologic DLTs were observed in two of the six patients (ipilimumab 3 mg/kg) in cohort 1, resulting in a reduction to ipilimumab 1 mg/kg.The dose level of 0.1 mg/kg was increased to N=12 without the use of DLT. IrAE included grade 1, 2, and 3 dermatitis (2), grade 4 colitis (1), and grade 1 hyperthyroidism (1). The overall survival rate was 72% (90% CI, 57–92) and the disease-free survival rate was 72%. Coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg expression was associated with decreased DFS (HR=5.6; 95% CI, 0.83–37.8; P=0.08). The combination of standard cetuximab and ipilimumab, when used with radiotherapy (RT), is administered at a dose of 1 mg/kg every 5 weeks for 4 doses. The treatment is manageable and provides acceptable survival without cytotoxic chemotherapy.