BACKGROUND: Symptoms of depression and anxiety can contribute to lower medical treatment adherence. Given that people with cystic fibrosis (PWCF) have higher rates of depressive and anxiety symptoms than those without cystic fibrosis (CF), this study examined factors that mediated the association between mental health and adherence. METHODS: Participants were 294 adults (M age=25 years) with CF who were enrolled in the Daily Care Check-in Validation Study. Participants completed in-clinic questionnaires that assessed depressive and anxiety symptoms, perceived barriers to self-management, and medication self-efficacy. Medication adherence was measured by pharmacy refill data. Parallel mediation models assessed perceived barriers and medication self-efficacy as mediators between depressive symptoms and adherence, and between anxiety symptoms and adherence. RESULTS: Perceived interference of barriers to self-management significantly mediated the association between depressive symptoms and adherence (β =-0.005, SE=0.002, 95 % CI [-0.009, -0.001]), and between anxiety symptoms and adherence (β=-0.005, SE=0.003, 95 % CI [-0.008, -0.001]). Additionally, self-efficacy significantly mediated the association between depressive symptoms and adherence (β=-0.004, SE=0.001, 95 % CI [-0.007, -0.002]), and between anxiety symptoms and adherence (β=-0.004, SE=0.001, 95 % CI [-0.007, -0.001]). CONCLUSIONS: This study found that when PWCF experienced mental health symptoms (either anxiety or depression), they were likely to report more interference from barriers to disease management or experience less medication self-efficacy, which was related to worse adherence. Building self-efficacy around taking medications may reduce the impact that mental health symptoms have on adherence. Care teams should also work with PWCF to minimize the impact of barriers on daily therapies.