The objectives of this study were to: (1) examine whether the smoking status of the Canadian population is associated with a reduction in health-related quality of life (HRQoL); (2) calculate the overall economic burden of loss in HRQoL using a commonly accepted $100,000 willingness-to-pay (WTP) threshold to gain one quality-adjusted life year (QALY); and (3) calculate the loss of HRQoL over a lifetime.We used the 2015 Canadian Community Health Survey. The variations in HRQoL were estimated using a multivariable generalized linear model. Total expected lifetime QALYs lost due to smoking were calculated by compounding the annual adjusted health utility loss associated with smoking across a respondent's remaining years of life expectancy stratified by age. A discount rate of 1.5% was applied to the analysis based on recent analysis of the costs of borrowing in Canada.Smoking is significantly associated with HRQoL loss. This study demonstrated that smoking is associated with a 0.05 and 0.01 reduction in Health Utilities Index Mark 3 (HUI3) score for current and former smokers, which also corresponds to a loss of 0.66 quality-adjusted life years in average, and also is associated with substantial individual and societal economic cost. The total lifetime economic burden of HUI3 loss per smoker was $65,935, yielding in the aggregate a societal burden of $1068.88 billion in the study population.Tobacco control, prevention and intervention not only will improve HRQoL but also will generate social returns on investment.