Annually, about 500,000 children are coping with life-limiting illnesses in the USA. Integrated pediatric palliative care program could benefit some of these children by improving their health-related quality of life (HRQOL). To measure the effect of pediatric palliative care programs on HRQOL, a valid and reliable tool must be identified. This study aimed to validate the psychometric properties of a generic HRQOL instrument, the Pediatric Quality of Life 4.0, for children with life-limiting illnesses. Analyses were conducted using telephone survey data collected from 266 parents whose Medicaid-enrolled children had life-limiting illnesses. Results of the analyses suggest the Pediatric Quality of Life 4.0 does not have valid psychometric properties for measuring HRQOL within this population. Our study documents several challenges in using the generic instrument to measure HRQOL in pediatric palliative care setting. We point out future directions to refine or develop HRQOL instruments for this population of vulnerable children.