The Youth Risk Behavior Surveillance System (YRBSS) monitors priority health-risk behaviors among US high school students. To better understand the ramifications of changing the YRBSS from paper-and-pencil to Web administration, in 2008 the Centers for Disease Control and Prevention conducted a study comparing these two modes of administration. Eighty-five schools in 15 states agreed to participate in the study. Within each participating school, four classrooms of students in grades 9 or 10 were randomly assigned to complete the Youth Risk Behavior Survey questionnaire in one of four conditions (in-class paper-and-pencil, in-class Web without programmed skip patterns, in-class Web with programmed skip patterns, and “on your own” Web without programmed skip patterns). Findings included less missing data for the paper-and-pencil condition (1.5% vs. 5.3%, 4.4%, 6.4%; p < .001), less perceived privacy and anonymity among respondents for the in-class Web conditions, and a lower response rate for the “on your own” Web condition than for in-class administration by either mode (28.0% vs. 91.2%, 90.1%, 91.4%; p < .001). Although Web administration might be useful for some surveys, these findings do not favor the use of a Web survey for the YRBSS.