The Pediatric Quality of Life Inventory (PedsQL) measures health-related quality of life, a growing area of research, particularly among individuals with disabilities. This research is necessary to fully understand the varied needs of the population and, ultimately, ensure that those needs are being met. The current study assessed the reliability and validity of the PedsQL in individuals with intellectual and developmental disabilities, including individuals with autism spectrum disorder. Participants included 359 caregivers of children, youth, and young adults with IDD. Caregivers completed the PedsQL 4.0 Generic Core Scales questions regarding the individual’s physical health and the Strengths and Difficulties Questionnaire. The PedsQL achieved excellent reliability across scales, and distinguished healthy individuals from those with chronic health conditions, as well as individuals with ASD from those without. Factor analysis confirmed a 5-factor model, with moderate to high criterion validity. The PedsQL shows sound psychometric properties and may be a useful tool to measure psychosocial functioning in this population.