We developed an interactive, customizable, Web-based program focused on the prevention of HIV, sexually transmitted infections, and hepatitis among youth. Results from a randomized, controlled trial with youth in treatment for substance use demonstrated that this Web-based tool, when provided as an adjunct to an educator-delivered prevention intervention, increased accurate prevention knowledge, increased intentions to carefully choose partners, and was perceived as significantly more useful relative to the educator-delivered intervention when provided alone. Results suggest this Web-based program may be effective and engaging and may increase the adoption of effective HIV and disease prevention science for youth. Limitations are discussed.