PURPOSEProton radiation therapy (PRT) may offer dosimetric and clinical benefit in the treatment of head and neck carcinoma of unknown primary (HNCUP). We sought to describe toxicity and quality of life (QOL) in patients with HNCUP treated with PRT. PATIENTS AND METHODSToxicity and QOL were prospectively tracked in patients with HNCUP from 2011 to 2019 after institutional review board approval. Patients received PRT to the mucosa of the nasopharynx, oropharynx, and bilateral cervical lymph nodes with sparing of the larynx and hypopharynx. Patient-reported outcomes were tracked with the MD Anderson Symptom Inventory-Head and Neck Module, the Functional Assessment of Cancer Therapy-Head and Neck, the MD Anderson Dysphagia Inventory, and the Xerostomia-Related QOL Scale. Primary study endpoints were the incidence of grade ≥ 3 (G3) toxicity and QOL patterns. RESULTSFourteen patients (median follow-up, 2 years) were evaluated. Most patients presented with human papillomavirus-positive disease (n = 12, 86%). Rates of G3 oral mucositis, xerostomia, and dermatitis were 7% (n = 1), 21% (n = 3), and 36% (n = 5), respectively. None required a gastrostomy. During PRT, QOL was reduced relative to baseline and recovered shortly after PRT. At 2 years after PRT, the local regional control, disease-free survival, and overall survival were 100% (among 7 patients at risk), 79% (among 6 patients at risk), and 90% (among 7 patients at risk), respectively. CONCLUSIONTherefore, PRT for HNCUP was associated with highly favorable dosimetric and clinical outcomes, including minimal oral mucositis, xerostomia, and dysphagia. Toxicity and QOL may be superior with PRT compared with conventional radiation therapy and PRT maintains equivalent oncologic control. Further prospective studies are needed to evaluate late effects and cost-effectiveness.