Background: Health risk behaviors among teenagers are common and schools considered as an ideal place for conducting preventions programs. Objectives: The current study aimed at determining the effect of interactive multimedia on knowledge and attitudes of high school teachers regarding prevention of students' health-risk behaviors. Patients and Methods: A total of 150 high school teachers were randomly assigned to intervention and control groups. Data were collected using a written test on knowledge and a rating scale for attitude towards health-risk behaviors. The educational contents were presented as booklets and multimedia CD-ROMs to the control and intervention groups, respectively. Pretest and posttest were administered before and four weeks after the intervention, respectively. Results: There was no significant difference between the intervention and control groups regarding the pre-and post-test knowledge and attitude mean scores. However, posttest mean scores of knowledge and attitude showed a significant increase in the two groups. Conclusions: Interactive multimedia, similar to booklets, could enhance teachers' knowledge and improve their attitudes toward the prevention of health-risk behaviors.