• Patients generally must have the psychological ability and general health that permits completion of the study requirements and required follow up.

• Women of childbearing potential and men who are sexually active should be willing and able to use medically acceptable forms of contraception throughout the treatment phase of the trial and until at least 60 days following the last study treatment.

• Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the primary (for T stage).

• Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving ≤ 4 nodes are permitted and considered as non-therapeutic nodal excisions.

• Immunohistochemical staining for p16 must be performed on tissue and documented in the pathology report(s) with reported result positive for p16.

• Clinical stage T1-T3, N0-N2c (AJCC, 7th ed.), which is equal to T1-T3, N0-2 (AJCC, 8th ed.) including no distant metastases based on the following diagnostic workup:

‣ General history and physical examination within 30 days prior to registration;

⁃ Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 60 days prior to registration;

⁃ One of the following combinations of imaging is required within 45 days prior to registration:

• A CT scan of the neck (with contrast) and a chest CT scan (with or without contrast);

∙ or an MRI of the neck (with contrast) and a chest CT scan (with or without contrast);

∙ or a CT scan of neck (with contrast) and a PET/CT of neck and chest (with or without contrast);

∙ or an MRI of the neck (with contrast) and a PET/CT of neck and chest (with or without contrast).

⁃ Note: A CT scan of neck and/or a PET/CT performed for the purposes of radiation planning may serve as both staging and planning tools.

• Patients will be asked about their personal smoking history prior to enrollment. Only active smokers with greater than 10 pack years will be excluded from the trial. The total number of pack years will be collected at baseline. Current smokers who wish to discontinue will be offered smoking cessation information, and if they are able to discontinue smoking prior to initiation of radiation therapy, they can remain eligible for the trial.

⁃ Number of pack-years = \[Frequency of smoking (number of cigarettes per day) × duration of cigarette smoking (years)\] / 20 Note: Twenty cigarettes is considered equivalent to one pack. The effect of non-cigarette tobacco products on the survival of patients with p16-positive oropharyngeal cancers is undefined.

• Zubrod Performance Status of 0-1 within 30 days prior to registration;

• Adequate hematologic function within 14 days prior to registration, defined as follows:

‣ Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;

⁃ Platelets ≥ 100,000 cells/mm3;

⁃ Hemoglobin ≥ 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.

• Adequate renal function within 14 days prior to registration, defined as follows:

‣ Serum creatinine \< 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min

• Adequate hepatic function within 14 days prior to registration defined as follows:

‣ Bilirubin \< 2 mg/dl;

⁃ AST or ALT \< 3 x the upper limit of normal.

• Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential