OBJECTIVE: The purpose of this study was to evaluate the performance of the Centers for Disease Control and Prevention's core Health-Related Quality of Life (HRQOL) scale using data from 5,520 public high school students. METHODS: The 1997 South Carolina Youth Risk Behavior Survey was the source of data. Chi-square analysis was applied to assess scale construct validity. Adjusted multiple logistic regression with selected tobacco and substance use variables was used to assess known-groups validity of the scale's Healthy Days index (items regarding poor physical and mental health days during the past 30 days). RESULTS: Construct validity was supported for the core HRQOL scale by the associations between self-perceived health and physical health, mental health, and activity limitation days. A greater number of poor physical health days, poor mental health days, or activity limitation days was associated with poorer self-perceived health (p<0.0001); however, correlation coefficients for the associations between self-perceived health and physical health days (r=0.24; p<0.001), self-perceived health and mental health days (r=0.26; p<0.0001), and self-perceived health and activity limitation days (r=0.23; p<0.0001), although significant, were low in magnitude. Logistic regression analyses conducted with the Healthy Days index revealed significant (p<0.05) HRQOL differences between users and non- users of tobacco and other substance use variables. As hypothesized, as the usage of each substance increased, reported poor HRQOL days increased, supporting the known- groups validity of the scale. CONCLUSIONS: This study provides preliminary evidence that the HRQOL scale items are valid and potentially useful for adolescent surveillance. The results, however, are mixed regarding the inclusion of self-perceived health as a measure of HRQOL for adolescents, given the low correlation coefficients for the associations between self-perceived health and the other HRQOL scale items. These results suggest that adolescents may be rating two separate dimensions of health when rating their self-perceived health and HRQOL. Further research is needed to confirm these findings in different adolescent populations.