The Secondary School Student Health Risk Survey measured the prevalence of sexual intercourse and illegal drug injection among a national probability sample of U.S. high school students and assessed their HIV-related knowledge and beliefs. Ninety-nine (81%) of the 122 selected schools and 8,098 (83%) of the eligible students participated. Nearly all high school students knew the major modes of HIV transmission. Three percent reported injecting illegal drugs, and 1% reported sharing needles used to inject drugs. In addition, 59% of students reported having sexual intercourse and, of students who reported having sexual intercourse, 40% reported having four or more sexual partners. HIV-related knowledge, beliefs, and behaviors among high school students suggest the need for school-based HIV education programs that help young people acquire the knowledge and skills to adopt and maintain behaviors that reduce risk of HIV infection and other related health problems.