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Health-related quality of life (HRQOL) is an important indicator of the burden of illness in moderate-to-severe plaque psoriasis. This study evaluated self-reported generic HRQOL among pediatric patients with moderate-to-severe plaque psoriasis based on pooled baseline clinical trial data and compared them to four common chronic diseases and to a healthy sample. The Pediatric Quality of Life Inventory Version 4.0 (PedsQL™ 4.0) Generic Core Scales was administered to 208 patients ages 4 to 17 years with stable, moderate-to-severe plaque psoriasis. Patients with moderate-to-severe plaque psoriasis were compared using one-sample t-tests to published PedsQL™ ( http://www.pedsql.org ) data on healthy children and pediatric patients with arthritis, psychiatric disorders, asthma, and diabetes. Pediatric patients with moderate-to-severe plaque psoriasis demonstrated significantly impaired physical, emotional, social, and school functioning in comparison to healthy children. The PedsQL™ Emotional and School Functioning Scales demonstrated the largest mean difference between the two groups (12.1, 11.1 points, respectively). In general, patients with plaque psoriasis demonstrated significantly more impaired generic HRQOL compared to patients with diabetes, comparable HRQOL to arthritis and asthma, and better HRQOL than psychiatric patients. In conclusion, the findings indicate that pediatric patients with moderate-to-severe plaque psoriasis have significantly impaired generic HRQOL in comparison to healthy children, and HRQOL generally comparable to other serious chronic diseases. These results demonstrate the significant negative impact of plaque psoriasis on the daily lives of these children from the patients' perspective.