Objective: The objective of the study was to evaluate the impact of #Tamojunto, a Brazilian adaptation of the Unplugged prevention program, on patterns of drug use among adolescents and to characterize their trajectories of drug use over time. Method: An in-cluster randomized controlled trial was conducted in 2014–2015 with 2 parallel arms (intervention and control). The intervention group attended 12 weekly classes of the #Tamojunto intervention. The control schools did not offer a prevention program. The target population was students attending seventh and eighth grades. The primary dichotomous outcome measures were use of drugs (any alcohol use, binge drinking, tobacco, marijuana, inhalants, and cocaine) in the past year assessed using a questionnaire before intervention and in 2 waves of follow-up (9 and 21 months). Results: A latent transition analysis in 6,391 students from 72 public schools in 6 Brazilian cities revealed 3 distinct patterns of drug use behavior: abstainers/low users (81.54% at baseline, 70.61% after 21 months), alcohol users/binge drinkers (16.65% at baseline, 21.45% after 21 months), and polydrug users (1.80% at baseline, 7.92% after 21 months). No differences in the probabilities of transitions between these drug use patterns were found between the intervention and control groups. The most likely trajectory was no transition between patterns, regardless of the intervention and baseline pattern. Conclusions: The intervention was not successful in changing adolescent drug use patterns over time, showing that the components of the Brazilian adaptation of the Unplugged prevention program should be reevaluated.