Variation in the CYP2A6 gene, which decreases the rate of nicotine metabolic inactivation, is associated with higher adult smoking cessation rates during clinical trials. We hypothesized that slow metabolism is associated with increased quitting during adolescence. White adolescent smokers (N=308, aged 12-17, 36.3% male) from a cohort study were genotyped for CYP2A6, resulting in 7.8% slow, 14.0% intermediate and 78.2% normal metabolizers. Overall, 144 smokers quit smoking, as indicated by being abstinent for at least 12 months. In logistic regression analyses, the odds ratio for quitting was 2.25 (95% confidence interval 1.05, 4.80; P=0.037) for slow metabolizers relative to normal metabolizers. A linear trend toward increased quitting with decreasing CYP2A6 activity was also observed (odds ratio=1.44, 95% confidence interval 1.02, 2.01; P=0.034). Thus, CYP2A6 slow metabolism is associated with increased adolescent smoking cessation, indicating that even early in the smoking history, genetic variation is influencing smoking cessation.