Background: As the population of people with CF (pwCF) continues to age, attention is shifting towards addressing the unique challenges teenagers and adults face, including substance use. Changing attitudes and legality regarding marijuana and CBD may influence their use among pwCF, but data on their prevalence, reasons for use, and administration methods are lacking. Objective: Investigate marijuana, cannabidiol (CBD), e-cigarette, and cigarette usage among pwCF and explore differences in demographics, disease severity, and CFTR modulator use between current and non-users. Methods: This cross-sectional study used a one-time electronic survey to assess marijuana, CBD, e-cigarette, and cigarette use in pwCF aged >13 years. Demographic and clinical characteristics were compared between current users and non-users. The association between current substance use and CFTR modulator use was analyzed using logistic regressions. Results: Among 226 participants, 29% used marijuana, 22% used CBD, 27% used e-cigarettes, and 22% used cigarettes. Current users of all substances were more likely to be college-educated, Black, or aged 29-39 years than non-users. Current e-cigarette users were 2.9 times more likely to use CFTR modulators (95% CI 0.98-11.00, p=0.08) and current marijuana users were 2.5 times more likely to use CFTR modulators compared to non-users, adjusted for confounders. Current users of CBD, e-cigarettes, and cigarettes were more likely to have an abnormal mental health screen compared to non-users. A high proportion of never-users of marijuana and CBD expressed interest in using. Conclusion: Substance use is more prevalent among pwCF than previously reported and needs to be addressed by healthcare providers.