Background Health related quality of life is the functional effect of a medical condition and/or its therapy upon a patient, and as such is particularly suitable for describing the general health of children. The objective of this study was to identify and confirm potential determinants of health-related quality of life in children aged 4-11 years in the general population in the Netherlands. Understanding such determinants may provide insights into more targeted public health policy. Methods As part of a population based cross sectional study, the Child Health Questionnaire (CHQ) Parental Form 28 was used to measure health-related quality of life in school-aged children in a general population sample. Parents of 10,651 children aged 4-11 years were interviewed from January 2001 to December 2009. Results Multivariate and regression analyses demonstrated a declined CHQ Physical Summary score for children who had >1 conditions, disorders or acute health complaints and who were greater consumers of healthcare; children with a non-western immigrant background; and children whose parents did not work. Lower CHQ Psychosocial Summary score was reported for children who had >1 conditions, disorders or acute health complaints, boys, children of single parents and obese children. Conclusion The best predictors of health-related quality of life are variables that describe use of health care and the number of disorders and health complaints. Nonetheless, a number of demographic, socio-economic and family/environmental determinants contribute to a child's health-related quality of life as well.