BACKGROUND: Cystic fibrosis (CF) is a progressive, life-shortening disease currently treated symptomatically. Among the consequences of daily treatments and long-term progression of the disease is significant discomfort and pain. This study measured pain systematically in adolescents with CF using a pain diary, and evaluated its associations with treatment adherence, psychological symptoms, and health-related quality of life (HRQOL). METHODS: This study was part of a larger, multi-center study. Ninety-five adolescents with a mean age of 15.8 were enrolled. A total of 413 online pain diaries were completed for 6 days following a routine clinic visit. Diaries measured pain intensity, location, duration, affective ratings, and coping responses. Adherence to pulmonary medications was measured using prescription refill data; other measures included ratings of depression, anxiety and HRQOL. RESULTS: Pain was reported by 74.5% of participants, generally in the mild range, averaging 2.1 on a 10-point scale. Daily pain ratings were highly variable both within and between participants. Pain was significantly associated with worse adherence, more psychological distress, and worse HRQOL. CONCLUSIONS: Results indicated that pain is a common problem for adolescents with CF and negatively affects their disease management, psychological symptoms and health outcomes. Routine assessment of pain and systematic studies of interventions to treat pain are recommended. Pediatr Pulmonol. 2015; 50:244-251. © 2014 Wiley Periodicals, Inc.