Objective: Platinum-based chemotherapies have been associated with debilitating treatment-related complications among patients with advanced squamous cell carcinoma of the head and neck (ASCCHN). This study evaluated the incidence and costs of such complications among ASCCHN patients undergoing radiotherapy alone versus platinum-based chemoradiotherapy. Methods: Using 2000-2006 data from the PharMetrics Patient-centric Database, this retrospective cohort study measured clinical practices, incidence rates, and costs of treatment-related complications including oral complications, dehydration, infection/fever, fatigue, malnutrition, nausea, neutropenia and anemia among ASCCHN patients undergoing radiotherapy alone or platinum-based chemoradiotherapy. Patients were identified if they had a SCCHN claim between June 30, 2000 and December 31, 2005 and an indication of a secondary malignant neoplasm (both based on ICD-9-CM diagnosis codes). Patients were assigned to a treatment-based cohort–radiotherapy only or platinum-based chemo-radiotherapy, and were followed for six months. Results: We identified 131 ASCCHN patients treated with radiotherapy alone and 90 patients treated with chemoradiotherapy, including 62 with cisplatin plus radiotherapy, 30 with carboplatin plus radiotherapy, and two with cisplatin and carboplatin plus radiotherapy. Patients undergoing chemo-radiotherapy were slightly younger than radiotherapy patients (mean ages: 54.1 and 56.1 years, respectively), were more likely to be male, and were less healthy, as evidenced by higher Charlson co-morbidity scores. We found significantly (P<0.001) higher rates of treatment-related complications among patients receiving chemo-radiotherapy (87%) compared with patients receiving only radiotherapy (51%). Mean per-patient costs associated with treatment-related complications were $10,632 higher among chemo-radiotherapy patients compared to radiotherapy patients (P=0.002). These costs comprised 18% of total costs during follow-up for chemo-radiotherapy patients and 9% of costs for radiotherapy patients. The most expensive complications were dehydration/electrolyte imbalance and oral complications. Conclusion: Our findings suggest that the excess incidence and costs of treatment-related complications associated with chemo-radiotherapy in ASCCHN are substantial. The emergence of safer treatments may alleviate this cost burden.