BackgroundThe influence of habitual physical activity and exercise capacity on health‐related quality of life (HRQoL) in people with cystic fibrosis (pwCF) is poorly characterized. This study investigated the influence of habitual physical activity, exercise capacity, lung function, and body mass index (BMI) on HRQoL in adolescent and adult pwCF.MethodSubjects were fitted with an accelerometer to determine habitual physical activity (steps/day), including time spent at different intensities, for up to 4 weeks. Then bicycle ergometry (maximal exercise capacity; Wpeak), lung function (percent predicted forced expiratory volume in 1 s, ppFEV1), BMI, and response to the Cystic Fibrosis Questionnaire‐Revised (CFQ‐R) were determined.ResultsSixty‐five pwCF participated in the study. Physically active pwCF had significantly higher ppFEV1 (p < .001) and exercise capacity (p < .001) than inactive pwCF, and had significantly higher scores on the CFQ‐R physical (p = .006), emotional (p = .015), role (p = .008), health (p = .006), and weight (p = .004) subscales. On multiple linear regression analysis, ppFEV1 and, to a lesser extent, exercise capacity, were the most important determinants of HRQoL in pwCF. Time spent in moderate‐to‐vigorous intensity physical activity did not influence any of the CFQ‐R subscales, whereas time spent in vigorous‐intensity influenced CFQ‐R scores for role (p = .007), body (p = .001), health (p = .009), and weight (p = .01).ConclusionHRQoL in adolescent and adult pwCF was influenced by several factors. Avoiding sedentary behavior and spending time in vigorous‐intensity levels positively influenced HRQoL, whereas the total number of steps per day played only a minor role in determining HRQoL. Both ppFEV1 and exercise capacity markedly influenced HRQoL.