ABSTRACT. Objective: Use of tobacco, alcohol, marijuana, and other drugs increases during the high school years, yet little is known about individual patterns over time, particularly patterns of contemporaneous multiple-substance use. This study examined trajectories of contemporaneous substance use and how individual and social factors differentially predict patterns of substance use. Method: Longitudinal trajectories of substance use were examined in a nationally representative sample of students (N = 2,512) over a 3-year period (10th through 12th grades) using latent class analysis. Individual, parental, and peer risk factors in 10th grade were examined in relation to membership in trajectory classes. Result: A five-class model was identified: nonusers (45.5%); tobacco, alcohol, and other drug users (9.2%); alcohol and other drug users (9.2%); increasing multiple-substance users (16.7%); and decreasing multiple-substance users (19.4%). Depressive symptoms at baseline were associated with a higher likelihood of membership in all classes except the increasing multiple-substance-user class, but the association becomes insignificant when social influence factors were adjusted. Parental-monitoring knowledge was associated with a lower likelihood of membership in all classes except increasing multiple-substance-user class, whereas perceived parental disapproval was associated with a lower likelihood of membership in the tobacco, alcohol, and other drug user class. Peer substance use was associated with a higher likelihood of membership in each of the substance use classes. Conclusions: The identified longitudinal profiles highlight the pervasiveness and dynamic patterns of contemporaneous multiple-substance use during 10th through 12th grades. Negative peer influence increased risk, whereas positive parenting behaviors decreased risk. The findings are consistent with the need to foster social influences and protective factors against adolescent substance use. (J. Stud. Alcohol Drugs, 76, 962-970, 2015) Received: March 4, 2015. Revision: July 7, 2015. This research (contract number HHSN267200800009C) was supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), with supplemental support from the National Institute on Drug Abuse (NIDA). The views and opinions expressed in this article are those of the authors and do not necessarily represent the views of NIDA, the NICHD, the National Institutes of Health, or any other governmental agency.*Correspondence may be sent to Ashley Brooks-Russell at the Department of Community and Behavioral Health, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, 13001 E. 17th Place B119, Bldg. 500, E3353, Aurora, CO 80045, or via email at...