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The authors' objective was to describe the effect of recurrent pain symptoms on the health-related quality of life (HRQOL) of children and adolescents with cystic fibrosis (CF). Frequent pain, independent of disease severity, was hypothesized to be associated with broad decrements in physical, psychological, and social functioning.Forty-six children and adolescents (mean age 12.9 years; 52% female) completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R) to assess their HRQOL and a retrospective pain interview to assess pain location, frequency, intensity, duration, and bother during a routine clinic visit. Forced expiratory volume in 1 second as percent of predicted (FEV1%) was recorded from medical charts to assess the children's disease severity.As hypothesized, pain symptoms were related to children's physical, emotional, and role functioning, CF-related symptoms, and overall perception of their health. Children with frequent pain had significantly reduced physical functioning, vitality, role limitations, and overall perceptions of their health, and increased eating disturbances, treatment burden, respiratory, and digestive symptoms compared with children with no pain or less frequent pain. After controlling for the effects of disease severity, pain frequency continued to predict children's HRQOL in each of these areas.Children with frequent CF-related pain experienced broad decrements in their HRQOL. These findings are similar to those found in other populations of children experiencing disease-related pain, suggesting a pervasive impact of pain on overall health and well-being. Future research is needed to evaluate treatments to reduce pain symptoms and improve HRQOL in children with cystic fibrosis.