BACKGROUND: Health-related quality of life (HRQOL) has received much attention in patients with cystic fibrosis (CF). The goal of this study was to evaluate the association between clinical, lung function, sleep quality, and polysomnographic variables with 2 HRQOL questionnaires, the shorter-version World Health Organization Quality of Life (WHOQOL-BREF) and Cystic Fibrosis Quality of Life (CFQOL) questionnaires, in adult subjects with CF. METHODS: In a cross-sectional study, 51 subjects underwent clinical evaluation and overnight polysomnography and answered WHOQOL-BREF, CFQOL, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale questionnaires. In addition, pulmonary function tests, 6-min walk tests, and echocardiography were performed. RESULTS: For WHOQOL-BREF scores, the sleep quality index was associated with the physical domain; the percent-of-predicted 6-min walk distance (6MWD) and sleepiness scale were associated with the psychological domain; the percent-of-predicted FEV1 and sleep quality index were associated with the social relationship domain; and the sleep quality index was associated with the environment domain. For CFQOL scores, age at diagnosis, clinical score, and sleep quality index were associated with the physical functioning domain; the percent-of-predicted 6MWD and pulmonary arterial systolic pressure were associated with the role domain; sex and sleep quality index were associated with the vitality domain; the apnea-hypopnea index was associated with the emotional functioning domain; sex and body mass index (BMI) were associated with the body image domain; the percent-of-predicted 6MWD and sleep quality index were associated with the health perception domain; age, sex, BMI, and arousal index were associated with the weight domain; age, sex, percent-of-predicted FEV1, percent-of-predicted 6MWD, and pulmonary arterial systolic pressure were associated with the respiratory symptom domain; and the clinical score was associated with the digestive symptom domain. CONCLUSIONS: The sleep quality index score, 6MWD, sleepiness scale score, and FEV1 were predictors of WHOQOL-BREF scores. Age at diagnosis, clinical score, sleep quality score, 6MWD, sex, apnea-hypopnea index, BMI, current age, arousal index, FEV1, and pulmonary arterial systolic pressure were predictors of CFQOL scores.