To explore, in a dose-escalation study, the feasibility of hyperbaric oxygen (HBO) treatments immediately before intensity modulated radiation therapy in conjunction with cisplatinum chemotherapy for squamous cell carcinoma of the head and neck (SCCHN). Eligible patients presented with SCCHN (stage III-IV [M0]), life expectancy >6 months, and Karnofsky performance status ≥70. Enrollees received intensity modulated radiation therapy, 70 Gy in 35 fractions over 7 weeks with weekly cisplatinum. Patients received HBO-100% oxygen, 2.4 atmospheres absolute (ATA) for 30 minutes-twice per week initially. Subsequent patients were escalated to 3 and then 5 times per week. Intensity modulated radiation therapy began within 15 minutes after HBO. Patients were followed for 2 years after RT with quality-of-life questionnaires (Performance Status Scale-Head and Neck Cancer and the Functional Assessment of Cancer Therapy-Head and Neck Cancer) and for 5+ years for local recurrence, distant metastases, disease-specific survival, and overall survival. Twelve subjects enrolled from 3 centers. Two withdrew during radiation therapy and 1 within 14 weeks after radiation therapy. The remaining 9 had primary oropharyngeal disease and were stage IVA (7) or IVB (2). No dose-limiting toxicities were observed with daily HBO. Two patients (22%) required pressure equalization tubes. The average time between HBO and radiation therapy was 8.5 minutes, with 2 of 231 administrations delivered beyond 15 minutes (0.5%). Per-protocol analysis showed a clinical complete response in 7 and a pathologic complete response without tumor in salvage neck dissections in 2. With minimum follow-up of 61 months, per-protocol 5-year overall survival was 100%, local recurrence 0%, and distant metastases 11%. Patient-reported outcomes for quality of life (Functional Assessment of Cancer Therapy-Head and Neck Cancer) were comparable to published results for chemoradiotherapy without HBO. While acknowledging the study's small size and early attrition of 3 patients, our in-depth review of the acquired data indicates the feasibility of combining HBO with chemoradiation.