Multiple studies have shown that Multisystemic Therapy (MST) is, at group level, an effective treatment for adolescents showing serious externalizing problem behavior. The current study expands previous research on MST by, first, examining whether subgroups of participants who respond differently to treatment could be identified. Second, we investigated if the different trajectories of change during MST could be predicted by individual (hostile attributions) and contextual (parental sense of parenting competence and deviant and prosocial peer involvement) pre-treatment factors. Participants were 147 adolescents (mean age = 15.91 years, 104 (71%) boys) and their parents who received MST. Pre-treatment assessment of the predictors and 5 monthly assessments of externalizing behavior during treatment took place using both adolescent and parents’ self-reports. Six distinct subgroups, showing different trajectories of change in externalizing problem behavior during MST, were identified. Two of the 6 trajectories of change showed a poor treatment response, as one class did not change in externalizing problem behavior and the other class even increased. The remaining 4 trajectories displayed a positive effect of MST, by showing a decrease in externalizing behavior. Most of these trajectories could be predicted by parental sense of parenting competence. Additionally, lower involvement with prosocial peers was a predictor of the group that appeared to be resistant to MST. Adolescents do respond differently to MST, which indicates the importance of personalizing treatment. Protective factors, such as parental sense of parenting competence and prosocial peers, seem to require additional attention in the first phase of MST.