Rationale \| Elective neck irradiation is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy. It is expected that elective neck irradiation can be omitted to one or both sides of the neck in 9 out of 10 patients with a clinically negative neck (cN0). For patients with clinically positive ipsilateral nodes (cN1-2b), it is expected that elective irradiation of the contralateral neck can be omitted in 7 out of 10 patients. This will enable better sparing of normal tissues from radiation and result in less permanent long-term radiation side effects with better quality of life. Methods/design \| This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with sentinel lymph node biopsy guided neck irradiation versus standard bilateral elective neck irradiation in 242 patients with cN0-N2b squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral elective neck irradiation is indicated. Patients randomized to the experimental-arm will undergo sentinel lymph node biopsy. Based on the histopathologic status of the sentinel lymph nodes, patients will receive no elective neck irradiation (if no nodal metastases found at both sides of the neck), unilateral neck irradiation only (if no nodal metastases found at contralateral side of the neck only) or bilateral neck irradiation (if nodal metastases found at both sides of the neck). Patients randomized to the control arm will not undergo sentinel lymph node biopsy but will receive standard bilateral elective neck irradiation. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment. Discussion \| If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care.