Comorbid problems often coincide in individuals with autism spectrum disorder (ASD). Many parent-mediated systemic interventions have been developed for children to address these comorbid problems, with varying success. This study presents a systemic parent-mediated intervention, The Essential 5®. The effects of this intervention on comorbid social, cognitive and emotional problems in children with ASD were measured with the Child Behavioral Checklist (CBCL). In this study 952 children (6–16 years) and their parents/caregivers participated. There was a significant reduction on the CBCL total scale after the intervention (F = 504,149; p < .001, η²=.347), both for boys and girls separately. The reduction was found on all scales. When the CBCL was analysed as a clinical DSM-scale, all scales significantly decreased after the intervention for the whole group and for boys and girls separately. Based on the CBCL normative data 60% of the children had t-scores below the clinical range at the end of the intervention, compared to 36.6% before the intervention (χ2 = 11.34, p < 0.01). Therefore, it can be concluded that The Essential 5® intervention is effective in reducing comorbid problem behavior in children with ASD. These results clearly invites for more research into the validity of this intervention.