Background: Elexacaftor/tezacaftor/ivacaftor (E/T/I), has broadened access to life-changing pharmacotherapy for people living with cystic fibrosis (plwCF). However, case reports suggest CFTR modulators may induce psychiatric adverse symptoms. To systematically examine this, we studied depression and anxiety symptoms before and after initiation of E/T/I. Methods: Patient Health Questionnaire-9 (PHQ-9, depression symptoms) and Generalized Anxiety Disorder-7 (GAD-7, anxiety symptoms) scores recorded in a clinic database were studied. Patients who had scores collected pre- and post-E/T/I initiation were included. Mean total score changes were calculated for each questionnaire, and regression analyses described associations between score changes and age, race, ethnicity, sex, CFTR mutation, and prior depression and/or anxiety diagnoses. Secondary analyses examined the possible confounding effects of the SARS-CoV-2 (COVID-19) pandemic. Results: Eighty-six patients were included. Mean GAD-7 and PHQ-9 total scores did not change from pre-initiation (4.90 ± 5.31 and 4.98 ± 5.77, respectively) to post-initiation (5.27 ± 5.59 and 4.82 ± 5.55, respectively). Although patients (N = 40) evaluated prior to the COVID-19 pandemic showed a significant worsening of GAD-7 scores post-E/T/I initiation, this difference was not observed in the overall cohort (N=92). Pre-existent anxiety, depression, or other clinical factors did not predict an increased risk of mental health symptoms post-E/T/I initiation. Conclusions: Treatment with E/T/I does not lead to changes in depression or anxiety symptoms at the population level. No clinical predictors were identified to stratify potential risk. Overall, these findings are reassuring for clinicians and pwCF when deciding about initiating E/T/I treatment.