Background. Tobacco use continues to be the leading global cause of preventable death. The majority of smokers begin using tobacco products at teen ages. The aims of this study were providing a methodology of Isfahan Tobacco Use Prevention Program and investigating the prevalence of tobacco use and its related factors. Method. It was a cross-sectional study among guidance and high school students in Isfahan province. Initiation, social, psychological (depression and self-efficacy), family, and attitudinal and belief factors and school policy toward smoking (cigarettes and water-pipe) were investigated. Saliva qutinin was given from 5% of participants for determination of accuracy of responses. A self-administered anonymous questionnaire was used for gathering all data. Results. Of all 5500 questionnaires distributed, about 5408 completed questionnaires were returned (with response rate of 98.3%). Of all participants, 2702 (50.0%) were girls and 2706 (50.0%) were boys. Respectively, 4811 (89.0%) and 597 (11.0%) were from urban and rural. Of all participants, 2445 (45.2%) were guidance school and 2962 (54.8%) were high school students. Conclusion. This study will provide a unique opportunity to study prevalence of smoking cigarettes and water-pipe (ghelyan) among guidance and high school students in Isfahan province and determine the role of initiation, social, psychological, family, and attitudinal and belief factors and school policy toward smoking.