Limited studies have investigated differential treatment responses to family-based treatment programs and subgroup trajectories in youth in a high-risk context. This study pioneered an examination of Multisystemic Therapy for Child Abuse and Neglect (MST-CAN) and built on prior research that identified subgroups with different psychopathologies. Participants included 208 parent-child dyads enrolled in the MST-CAN evaluation in Switzerland. Parents reported their children's (Mage = 10.27years, SDage = 3.5, 44.2% girls, 55.8% boys, 98.6% White) emotional and behavioral problems. Longitudinal data were examined to analyze the differential changes within the pre- and post-treatment (T1 and T2) subgroups. The T1 cluster and T2 cluster were cross-tabulated to examine changes in the symptom class over time. Overall, the treatment proved to be highly beneficial. Subgroup analyses revealed that four out of the five subgroups (80%) showed positive changes in at least two outcome measures. The treatment was most successful for children with externalizing symptoms. Children with multiple symptoms also showed improvements across different symptoms. Regarding specific symptoms, children with anxious-avoidant symptoms benefited from the treatment. Additionally, the treatment was beneficial for children with normative emotions and behavior. Meanwhile, the treatment did not have any significant effects for children with internalizing symptoms. Notably, child neglect was reduced in three (60%) subgroups. The symptom class remained stable across time for children with externalizing and multiple symptoms. Ultimately, MST-CAN reduced emotional and behavioral problems and child neglect in most families. Understanding children's differential treatment responses to complex treatment programs is essential to adequately address different needs.