Adolescence is an important stage of life when health behaviors and attitudes are established. The purpose of this research was to assess health risk behaviors among Guatemalan students in both an urban and rural school. Items were adapted from the Global School-based Student Health Survey and were used to measure and compare the prevalence of risk behaviors between these two demographically and culturally distant school-based samples. In general, the prevalence of adolescent health risk behaviors in both schools was lower than other Latin American countries. Many health risk behaviors were associated with location (urban vs. rural settings) and/or gender. Tobacco use, alcohol use, and sexual activity were higher among urban students. Boys were more likely than girls to use alcohol, use tobacco, and be sexually active. In addition, the prevalence of mental health problems was higher among girls and rural students. These findings imply that measures should be taken to design effective and appropriate health strategies for adolescents attending these schools. Health promotion programs in schools and communities should assist the youth in developing positive health behaviors and cultivating healthy lifestyles in an effort to reduce risk behaviors among adolescent populations. Further research is needed to extend our understanding of risk factors of health behavior in these adolescent populations and to identify effective preventative approaches and strategies that specifically cater to the location and culture of the students.