BACKGROUND: Relationships between smoking and health-related quality of life (HRQoL) in the general population remain unclear. OBJECTIVES: To quantify the independent associations between smoking patterns and HRQoL and to identify any threshold or non-linear tendencies in these associations. METHODS: A national representative, cross-sectional household survey of the French general non institutionalized population included 7525 men and 8486 women, aged 25-64 year in 2003. Scores on the eight subscales of the Medical Outcomes Study 36-item Short Form were the primary outcomes. Linear regression analyses were used to evaluate the associations between HRQoL and smoking history, quantity of smoking and smoking cessation while controlling for various socio-economic variables, depression, alcohol dependence and pathological conditions. Analyses were conducted in 2013. RESULTS: Independent associations between smoking and HRQoL were found, including small positive associations for occasional or light smoking (up to 5 cigarettes per day), and larger and diffuse negative associations above this threshold. Much weaker associations and higher thresholds for negative HRQoL were found for women than for men. For ex-smokers of both genders, HRQoL was found to be better between 2 and 5 years after quitting. CONCLUSIONS: Smoking was independently related to HRQoL, with large differences according to the pattern and quantity of smoking, and to gender. These results may have considerable relevance both for public health action and care of smokers.