ARTICLE ABSTRACTBackground: Some studies suggest smoking may result in poorer clinical outcomes in head and neck cancer, but the evidence is heterogeneous and some of it is poor quality. In a large, population-based, study we investigated: (i) whether smoking at diagnosis is an independent prognostic factor for cancer-specific survival in head and neck cancer; and (ii) whether the association varies by site and treatment.Methods: Head and neck cancers (ICD10 C01-C14, and C30–32) diagnosed from 1994 to 2009 were abstracted from the National Cancer Registry Ireland, and classified by smoking status at diagnosis. Follow-up was for 5 years or until December 31, 2010. Multivariate Cox proportional hazards models were used to compare cancer-specific death rates in current, ex-, and never smokers. Subgroup analyses by site and treatment were conducted.Results: In total, 5,652 head and neck cancers were included. At diagnosis, 24% were never smokers, 20% ex-smokers, and 56% current smokers. Compared with never smokers, current smokers had a significantly raised death rate from cancer [multivariate HR, 1.36; 95% confidence interval (CI), 1.21–1.53]. The association was similar after restriction to squamous cell tumors. A significantly increased cancer-related death rate was seen for current smokers with oral cavity, pharyngeal, and laryngeal cancers. The association was stronger in surgically treated patients [HR, 1.49; 95% CI, 1.25–1.79; P(interaction) = 0.01]. Neither radiotherapy nor chemotherapy modified the effect of smoking.Conclusions: Patients with head and neck cancer who smoke at diagnosis have a significantly increased cancer death rate.Impact: Greater efforts are needed to encourage and support smoking cessation in those at risk of, and diagnosed with, head and neck cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2579–90. ©2014 AACR.