Background International consensus statements on depression and anxiety in adolescents and adults with CF recommend assessment for comorbid substance misuse. However, at CF centers, the frequency and impact of substance misuse have not been well characterized, and best practices for prevention, identification, and evidence-based treatment have not been routinely implemented. Methods Medical records of 148 adults with CF over 3 years were reviewed to determine the prevalence of substance misuse (alcohol or opiates) and its relationship with clinical variables and healthcare utilization. Independent-sample t-test for continuous outcomes and chi-square test for binary outcomes were used to compare groups with and without substance misuse. Results Substance misuse was documented in 28 (19%) adults with CF, equally distributed between alcohol (n=13) and opiates (n=15). Adults with substance misuse were more likely to be male. The prevalence of diagnosed anxiety and depression did not differ significantly between groups, but those with substance misuse had more severe anxiety (GAD-7: 10.0±6.1 vs. 3.3±4.4; p<0.001) and depressive symptoms (PHQ-9: 10.4±6.5 vs. 4.0±4.8; p<0.001). Adults with substance misuse had higher annual rates of missed outpatient CF visits and inpatient hospitalizations, with hospital admissions of longer mean duration. Conclusions In adults with CF, substance misuse is common and is associated with adverse indicators of emotional and physical health and service utilization, suggesting that systematic approaches to addressing substance misuse in CF clinics should be considered. Prospective, longitudinal study is warranted to elucidate the complex relationships between depression, anxiety, substance misuse, and health outcomes in individuals with CF.