ABSTRACT: BACKGROUND:Although obesity and mental health disorders are two major public health problems in adolescents that affect academic performance, few rigorously designed experimental studies have been conducted in high schools. PURPOSE:The goal of the study was to test the efficacy of the COPE (Creating Opportunities for Personal Empowerment) Healthy Lifestyles TEEN (Thinking, Emotions, Exercise, Nutrition) Program, versus an attention control program (Healthy Teens) on: healthy lifestyle behaviors, BMI, mental health, social skills, and academic performance of high school adolescents immediately after and at 6 months post-intervention. DESIGN:A cluster RCT was conducted. Data were collected from January 2010 to May of 2012 and analyzed in 2012-2013. SETTING/PARTICIPANTS:A total of 779 culturally diverse adolescents in the U.S. Southwest participated in the trial. INTERVENTION:COPE was a cognitive-behavioral skills-building intervention with 20 minutes of physical activity integrated into a health course, taught by teachers once a week for 15 weeks. The attention control program was a 15-session, 15-week program that covered common health topics. MAIN OUTCOME MEASURES:Primary outcomes assessed immediately after and 6 months post-intervention were healthy lifestyle behaviors and BMI. Secondary outcomes included mental health, alcohol and drug use, social skills, and academic performance. RESULTS:Post-intervention, COPE teens had a greater number of steps per day (p=0.03) and a lower BMI (p=0.01) than did those in Healthy Teens, and higher average scores on all Social Skills Rating System subscales (p-values <0.05). Teens in the COPE group with extremely elevated depression scores at pre-intervention had significantly lower depression scores than the Healthy Teens group (p=0.02). Alcohol use was 12.96% in the COPE group and 19.94% in the Healthy Teens group (p=0.04). COPE teens had higher health course grades than did control teens. At 6 months post-intervention, COPE teens had a lower mean BMI than teens in Healthy Teens (COPE=24.72, Healthy Teens=25.05, adjusted M=-0.34, 95% CI=-0.56, -0.11). The proportion of those overweight was significantly different from pre-intervention to 6-month follow-up (chi-square=4.69, p=0.03), with COPE decreasing the proportion of overweight teens, versus an increase in overweight in control adolescents. There also was a trend for COPE Teens to report less alcohol use at 6 months (p=0.06). CONCLUSIONS:COPE can improve short- and more long-term outcomes in high school teens. TRIAL REGISTRATION:This study is registered at www.clinicaltrials.gov NCT01704768.