In paediatric research, Health-Related Quality-of-Life (HRQoL) has received increasing recognition as an important health outcome. This study aimed to investigate the nature and prevalence of HRQoL problems in children with different chronic diseases. Data were available on 318 children aged 8-11 years with different diseases: congenital heart disease (n = 50); coeliac disease (n = 105); asthma (n = 32); cancer (n = 23); juvenile chronic arthritis (n = 45); children with capillary haemangioma (n = 25) and severe meningococcal disease (n = 38). They all answered a validated generic instrument [TNO-AZL Children's Quality of life questionnaire] (TACQoL), in the outpatient clinic or at home. Analyses of variance were performed to investigate differences in mean scores for children with chronic conditions in comparison to healthy children. Prevalence of children at risk for substantial HRQoL problems was based on the 25th percentile in the norm population. In comparison to healthy children, only a small number of differences were found in mean scores of children studied. In contrast, prevalence of HRQoL problems in children with chronic diseases was higher in several domains. It is concluded that using an indicator variable of the norm 25th percentile seems important in identifying at-risk children with chronic disease.