Abstract Background: Increased age and greater comorbidity are independent predictors of worse survival in nasopharyngeal and squamous cell cancers of the head and neck (HNC). The Charlson Comorbidity Index (CCI) provides a quantitative measure of comorbidity that can be abstracted from medical charts. We evaluated the role of anatomic subsite, smoking, alcohol, demographic and other variables on the impact of overall survival (OS) in HNC. Methods: Retrospective chart review was performed for 4689 HNC patients identified by the Princess Margaret Hospital and Ontario Cancer Registries (Toronto, Canada), between 2000 and 2010. Demographic (age, gender, occupation, marital status), and histologic variables were abstracted in addition to smoking and drinking consumption (current, former, never) and quantity (cigarettes: pack-years; alcohol usage: non/light, moderate, and heavy). CCI were categorized as no comorbidities (CCI 0), mild (CCI 1-2), moderate (CCI 3-4), and severe comorbidity (CCI 5+), respectively. HPV status in oropharyngeal tumors was assessed using p16 immunohistochemistry. Results: The population was mostly male (73%), married/common-law (71%), and median 63 years of age. Disease site consisted of 35% oral cavity, 28% oropharynx, 29% larynx, 6% hypopharynx, and 3% nasopharynx. Most tumors were stage III/IV (67%) and moderately differentiated (65%). Patients were categorized with 7% severe, 17% moderate, 47% mild, and 30% with no comorbidity. 79% of patients were ever-smokers and 84% were ever-drinkers. 481/688 OPC tumors were HPV+. Overall survival (OS) was better in younger patients (HR 1.03 per year, p < 0.0001), and those in married/common-law relationships (HR 1.48, p < 0.001). Greater comorbidity was associated with poorer OS: HR 1.5 (p < 0.0001), 2.0 (p < 0.0001), and 2.4 (p < 0.0001) for mild, moderate, and severe comorbidity, respectively. Univariately, oropharyngeal cancer had superior OS than cancers of the hypopharynx (HR 2.3, p < 0.0001) and oral cavity (HR 1.2, p = 0.006) but not the larynx (HR 0.97, p = 0.59) and worse OS than cancers of the nasopharynx (HR 0.54, p = 0.001). Advanced overall TNM stage was associated with poorer OS (HR 2.42, p < 0.0001), but grade was not significantly associated with survival. In terms of treatment, surgery alone (HR 0.63, p < 0.0001), surgery with post-operative radiation (HR 0.82, p = 0.004), and surgery followed by chemoradiotherapy (HR 0.76, p = 0.02) resulted in better OS than radiation alone. Heavier smoking and alcohol consumption resulted in poorer OS. For oropharyngeal cancer patients alone, HPV positivity improved OS (HR 0.30, p < 0.0001). Conclusion: In addition to stage, other important factors including social, demographic, treatment, histologic, and comorbidity variables also impact survival, and should be considered as prognostic factors in analyses of HNC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 666. doi:1538-7445.AM2012-666