Background: Multiple disabilities represent separate entities that cannot be reduced to the sum of disabilities or the main disability. This study compared the health-related quality of life (HRQoL) of children and adolescents with multiple disabilities and those with one developmental disability. We further assessed how comorbidities and guardianship type affected HRQoL. Method: On a sample of 190 children and adolescents with developmental disabilities aged 2-18 years (mean age 11.19 years, SD 3.76), we evaluated HRQoL using the PedsQL 4.0 Generic Core Scale (parent proxy-reports). Results: Participants with multiple disabilities and participants with one developmental disability statistically significantly differed in all domains of HRQoL, except for emotional functioning. Multiple disabilities resulted in a lower HRQoL. Comorbidities like epilepsy diminished participants' HRQoL. Guardianship type did not affect HRQoL. Conclusions: Disability complexity affects HRQoL. Since each impairment increases difficulties in daily functioning, all existing disorders need to be considered when planning services for children with disabilities.