To assess health-related quality of life (HRQoL) across three renal replacement therapy modalities (preemptive transplant, non-preemptive transplant, and dialysis) in comparison with the healthy norm and other chronic health conditions, and to explore related patient factors. All prevalent end-stage renal disease (ESRD) patients aged 8-18 years who spent at least 6 months on their current treatment modality in the Netherlands, Belgium, and part of Germany were approached to complete the Pediatric Quality of Life Inventory 4.0 (PedsQL (TM)) questionnaire. We determined the differences between groups on PedsQL (TM) mean scores, the proportion of children with an impaired HRQoL (ae<yen> 1 SD lower than the healthy norm), the proportion of problems on individual items of the PedsQL (TM), and the effect of time on current treatment. Linear regression models were used to explore determinants of HRQoL. 192 out of 278 patients (20% preemptive transplant, 58% non-preemptive transplant, 22% dialysis) filled in the PedsQL (TM) (response rate 69%). Independent of treatment modality, patients had significantly lower mean scores and consequently higher proportions of impaired HRQoL on almost all domains compared to the healthy norm and other chronic health conditions. Patients with a preemptive transplant only reported higher scores on physical health compared to the other treatment modalities. Having comorbidities was the most important determinant associated with lower HRQoL scores. Dialysis and renal transplantation both have a severe impact on the HRQoL of children with ESRD. Physicians should be aware of this continuous burden. Furthermore, to develop tailored interventions for children with ESRD, qualitative studies are needed to gain more insight in the determinants of HRQoL in the different treatment modalities.