Objective: To explore the relationship of multiple-vitamin supplement use with selected food groups, physical activity, lifestyle behaviors, and weight status. Subjects and Methods: Two thousand seven hundred sixty-one adolescents in the 12th grade who participated in the fourth Child and Adolescent Trial for Cardiovascular Health study had height and weight measured and completed health behavior survey and food frequency questionnaires. Logistic regression models were used to determine the likelihood of supplement use with health and activity behaviors and dietary intake. Results: Prevalence of multiple-vitamin supplement use among adolescents was 25% and varied by sex and race/ethnicity. Supplement users had higher mean daily intakes of most food groups, but lower intakes of total fat and saturated fat than nonusers. Higher food index scores were positively associated with the likelihood of using multiple-vitamin supplements. Supplement users were more likely to be physically active, participate in team and organized sports, and less likely to be overweight and to watch more than an hour of television per day. Conclusions: Adolescents who use multiple vitamin supplements have more healthful dietary and lifestyle behaviors than nonusers. Further study on supplement use by adolescents, including other types of supplements used and reasons for use, is warranted.