The purpose of this mixed methods study was to examine the effect of a multiple high-risk behaviors prevention program applied comprehensively throughout an entire school-system involving universal, selective, and indicated levels of students at a local private high school during a 4-year period. The prevention program was created based upon the key elements of effective prevention programming (Tobler et al., 2000) and the need to address the growing variety of high-risk behaviors youth face today (Sussman et al., 2010). Quantitative survey data and qualitative interview data were collected and analyzed according to Collins, Onwuegbuzie, and Sutton's (2006) 13-step mixed methods research process. A methodological framework of pragmatism-of-the middle and communities of practice approaches under the umbrella of dialectical pluralism were used (Denscombe, 2008; Johnson, 2012; Johnson & Onwuegbuzie, 2004). In addition, three theoretical frameworks were utilized: (a) ecological systems theory (Bronfenbrenner, 1979), (b) social learning theory (Akers, 1973; Bandura, 1977), and (c) stages of change theory (Prochaska & DiClemente, 1982). Quantitative results indicated seven out of 15 high-risk behaviors statistically significantly decreased throughout the 4-year study when compared to the pretest year data six involved alcohol and drugs. However, many of the non-substance use high-risk behaviors targeted displayed erratic prevalence rate patterns. Qualitative results of the 12 students interviewed yielded 12 main themes (and three subthemes) regarding student experiences with high-risk behaviors and the school's prevention efforts: (a) party school reputation (historically more lenient); (b) never used but know it is there; (c) primary focus on alcohol and drugs (drug testing as part of the program); (d) positive perceived effect of the program (drug testing effect); (e) complaints about programming; (f) choosing to engage with friends; (g) curiosity; (h) saying no because of parents; (i) seeing negative effects in others; (j) positive parental influence; (k) media influence; and (l) self-agency. The qualitative data validated the idea that the prevention programming placed heavier emphasis on alcohol and drugs than on other high-risk behaviors. Thus, the frequency and intensity of programming for non-substance use behaviors should be increased to at least equal that of the substance-use behaviors. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]