Background: The US Office of Adolescent Health (OAH) funded studies of teen pregnancy and sexually transmitted infection (STI) prevention programs in 2010. The results of a 5-year OAH study conducted in the state of Hawai'i with middle school youth has implications for school leaders in the selection and implementation of comprehensive sex education curricula yielding positive outcomes for youth. Methods: A cluster randomized controlled trial was conducted across 34 middle school in the state of Hawai'i with 1783 student participants in pre-, post-, and 1-year follow-up surveys to determine effectiveness of a culturally responsive teen pregnancy prevention curriculum, called Pono Choices, specifically developed for youth in Hawai'i. Results: Students receiving the Pono Choices curriculum had significantly higher rates of knowledge gains than students in control schools, although there were no statistically significant differences in initiation of sexual activity between the groups at the 1-year follow-up. Teachers implemented the curriculum at high rates of adherence to fidelity making this a model for implementation. Conclusions: Knowledge and retention of medically accurate teen pregnancy and STI prevention information can be attributed to implementation of a comprehensive program with attention to factors such as fidelity, program quality, engagement, and dosage.