AIM: We investigated the relationship between sex (genetic/biological) and gender (environmental/cultural) factors in relation to adolescent tobacco smoking. METHODS: A representative sample of 11,582 students from French secondary public schools participated in the study by completing a self-administered, standardised questionnaire. RESULTS: Using the WHO classification for smoking in the youth, 15.6% of the adolescents were regular smokers, 7.7% occasional smokers, 17.9% experimental smokers and 4.8% ex-smokers, with no statistically significant gender difference. Taking non-smoking as a reference, puberty had a much greater effect on the likelihood of being a regular smoker [OR = 18.0 (95% Confidence Interval: 9.6-32)] than of being an experimental/occasional smoker [OR = 3.7 (2.9-4.6)] among girls. For boys, the effect of puberty was not as great [OR = 4.7 (3.5-6.5)] for regular vs. [OR = 2.1 (1.8-2.5)] for experimental/occasional smokers). Similarly, illicit drug use had a larger effect on the likelihood of being regular smoker vs. non-smoker [OR = 15.0 (12.0-20.0) in boys and 12 (8.8-16.0) in girls] than of being experimental/occasional smoker vs. a non-smoker [OR = 4.8 (3.7-6.1) and 2.9 (2.1-3.9) respectively]. Other factors related to regular smoking were exposure to passive smoking and regular alcohol consumption. Living with both parents was a protective factor for life and regular smoking in both genders. CONCLUSIONS: Our results show that influential factors of sex-related (puberty), gender-specific (environmental tobacco smoking, alcohol consumption, drug abuse) or sex/gender (regular sexual intercourse) are related to the smoking behaviour in French adolescents.