Public health researchers and practitioners emphasize the need for effective, adoptable, and available youth smoking cessation interventions. Scarce resources demand that such interventions also be cost effective. This study describes a cost-effectiveness analysis (CEA) of the American Lung Association's Not On Tobacco (N-O-T) national and international teen smoking cessation program. N-O-T has been rigorously evaluated as an effective and adoptable program, and was recently found to be the most frequently-used teen smoking cessation program in the nation. N-O-T studies show intent-to-treat quit rates between 15% and 19%, among the highest reported in the literature. The current CEA resulted from a 2-year state-wide demonstration study in Florida, comparing the effectiveness of N-O-T with a 20-min brief intervention (BI). The CEA utilized a Markov transition model of decision analysis to explain stage progression of smoking cessation among participants from the age of 17 to 25 years. The Markov simulation predicted that out of a cohort of 100 N-O-T students, 10 will quit smoking and remain smoke-free at the age of 25 years and 14 will reduce smoking, resulting in 102.22 life years saved and a total of 20.11 years discounted life years (DLY) saved. Among BI youth, six will quit smoking and nine will reduce, indicating 64.31 life years saved and a total 12.65 DLY saved. The incremental DLY saved is 7.46 years. Results indicate that N-O-T is a very cost-effective option school-based smoking cessation, as cost effective as school-based primary tobacco prevention, and potentially more cost effective than adult tobacco use cessation.