The purpose of this study was to examine the relationship of HIV knowledge, demographics, and psychosocial factors with HIV risk behavior among high school students (N = 805) in urban and rural regions of Ecuador. Forty-three percent of the participants reported being sexually experienced. Of the sexually experienced participants, 50% reported never using condoms for intercourse, and 70% did not use condoms at last intercourse. A small minority of the sample felt that they were at risk for contracting HIV (18.5%). Educational aspirations past high school and residence in an urban area were significantly associated with decreased HIV risk (condom use at last intercourse and abstinence). High self-efficacy for condom use and strong refusal skills to unsafe sex were also significantly associated with decreased HIV risk. Consistent with prior research, the participants that reported their peers were sexually experienced were significantly more likely to have had sex. The discussion focuses on the use of interventions and education for promoting safer sexual behavior among Ecuadorian adolescents.