Background: Multiple studies have highlighted the negative outcomes associated with smoking during radiation (XRT) for locally advanced head and neck cancer. However, there has been little research investigating the potential benefit of smoking cessation prior to XRT and the effect on response rates, relapse, distant metastases, secondary malignancies, and overall survival. Methods: We reviewed 680 patients at the University of Texas MD Anderson Cancer Center from 2005-2012 with locally advanced head and neck cancer undergoing XRT. 127 were referred to the Tobacco Treatment Program (TTP) based on provider referrals, self-referrals, or screening. Of those referred and retrospectively reviewed, 89 were identified as current smokers and 41 of them participated in the TTP for smoking cessation. Among these 89 patients, 50 patients (18 participated in the TTP) quit smoking prior to XRT and 29 patients (19 participated in the TTP) continued to smoke, which are referred to as Quitters and Smokers, respectively. 10 patients (2 participated in the TTP) had incomplete data and were excluded from further analysis. Results: Quitters had 100% complete response (CR) on initial assessment following XRT. 7/50 (14%) developed relapsed disease with 4 local recurrences (LR) and 3 distant metastases (DM). 6/50 (12%) developed secondary malignancies. By contrast, Smokers had 96.5% CR on initial assessment following XRT. 8/29 (27.5%) developed relapsed disease with 6 LR and 2 DM. 6/29 (20.6%) developed secondary malignancies. The median follow ups for Quitters and Smokers were 57.5 and 54 months with overall survival rates of 82% and 79%, respectively. Conclusions: Current smokers that achieved smoking cessation prior to XRT demonstrated lower rates of relapse, DM, and secondary malignancies compared to those that continued to smoke. Thus, smoking cessation is an integral part of head and neck cancer treatment and needs to be further incorporated in cancer care to improve cancer treatment outcomes. As a future direction, a comparable group of patients who did not smoke from the same time range will be compared for response rates, LR, DM, secondary malignancies, and survival.