• Pathologically confirmed head and neck squamous cell carcinoma of the oral cavity, oropharynx, larynx, hypopharynx, sinus, or lymph nodes of the neck of unknown primary.

• Planned for curative intent postoperative radiotherapy based on pathologic risk factors.

‣ Patients with non-HPV-mediated oropharyngeal squamous cell carcinoma or non-oropharyngeal squamous cell carcinoma must have at least one of the following: pathologic tumor classification pT3-4, multiple lymph nodes involved with cancer, perineural invasion, lymphovascular invasion, close margins (within 2 mm for oropharyngeal cancer status post transoral resection; within 5 mm for all others) or cleared margins (initially positive, subsequently cleared in an additional specimen), extranodal extension (any extent), or positive surgical margins.

⁃ Patients with HPV-mediated oropharyngeal squamous cell carcinoma must have at least one of the following pathologic risk factors: extranodal extension (any extent), positive surgical margins, or more than 4 lymph nodes involved with cancer.

• Complete macroscopic surgical resection with curative intent for HNSCC with an anticipated interval between the primary surgical resection and initiation of postoperative radiotherapy greater than 42 days but less than or equal to 112 days from surgery. Note: the start date of the time to initiation of PORT is the first (primary) surgical resection. This does not include diagnostic procedures (e.g., biopsy, diagnostic tonsillectomy) or any subsequent surgical interventions for any reason (e.g., wound complications).

• Age ≥ 18 years at the time of enrollment.

• ECOG performance status of 0-1.

• Ability to understand and the willingness to sign an IRB-approved informed consent document directly, in English or Spanish, and to complete study-related forms and activities.