•Quitting smoking after HNSCC diagnosis increases therapy response by about 4-fold.•Quitting after diagnosis reduces cancer recurrence and increases disease-free survival.•Smokers at cancer diagnosis who quit before therapy increase long-term survival.•Smoke cessation after cancer is predictive of higher therapy efficacy and survival. Head and neck squamous cell carcinoma (HNSCC) patients who are current smokers when diagnosed have inferior clinical outcomes compared to never-smokers or previous smokers. However, the impact of quitting after HNSCC diagnosis has not been quantified. In this retrospective, case-control study (n = 134), the odds of complete response to first-line therapy were 3.7 times higher among smokers at diagnosis who quit before treatment initiation (quitters; n = 55) than among those continuing to smoke (p = 0.03). Disease-free survival was also higher among quitters (aHR, 0.33; 95 % CI, 0.12–0.90; p = 0.029). Quitters were 67 % less likely to die of all causes than active smokers (aHR, 0.33; 95 % CI, 0.15–0.71; p = 0.004). These data show for the first time that, smoking cessation after HNSCC diagnosis is predictive of higher therapy efficacy and long-term survival.