Abstract Background and Objectives Quality of life measurements can help to estimate the well-being of chronically ill patients, and disclose discrepancies in perception between physicians and patients that might otherwise interfere with the effectiveness of treatment. The objective was to investigate the differences in perception of quality of life between parents of chronically ill children and pediatricians. Methods A cross-sectional study was conducted in four tertiary pediatric care centers in The Netherlands. The Health Utilities Index mark 3 (HUI3) was used by 37 pediatricians and 279 parents of patients (children aged 1 to 17 years) with cystic fibrosis admitted either in daycare or for a pneumonia, or patients with newly diagnosed acute lymphoblastic leukemia, juvenile idiopathic arthritis, or asthma. Results Differences in perception of quality of life between parents and pediatricians appeared to be dependent of the disease. In patients with acute lymphoblastic leukemia (OR 7.4; [95% CI 2.88–18.97], juvenile idiopathic arthritis (4.7; [95% CI 2.00–11.22]), and asthma (2.3; [95% CI 1.13–4.69]) a difference in perception was more likely to occur than in patients with cystic fibrosis admitted in daycare. Conclusion At the onset of a chronic disease, the parents of pediatric patients may be misunderstood by health care professionals, especially in subjective attributes. Assessment of quality of life may contribute to better understanding between pediatricians and parents, and thus may even enhance compliance and treatment effects.