Introduction <p>Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are the cornerstone treatment for CF, but nonadherence can reduce their effect.</p> <p>Long-term adherence data on elexacaftor/tezacaftor/ivacaftor (ETI) combined with the evening dose ivacaftor (IVA) are lacking. The aim of this study was to determine 3-year adherence to ETI and IVA based on pharmacy refill data.</p> Methods <p>A retrospective observational cohort study was conducted using pharmacy refill data. Medication adherence was calculated using the proportion of days covered (PDC). The primary outcome was the PDC for ETI and IVA, which were calculated at 1, 2, and 3 years after initiating ETI and IVA. The secondary outcome was the proportion of non-adherent people with CF (pwCF), defined as having a PDC &lt; 0.8.</p> Results <p>A total of 128 pwCF were included (75 male [59%], mean age 28.8 ± 15.5 years). At year 1, the PDCs for ETI and IVA (<i>N</i> = 128 and 112) were (median, range) 0.98 (0.69–1.0) and 0.98 (0.68–1.0); at 2 years (<i>N</i> = 105 and 95), 0.99 (0.54–1.0) and 1.0 (0.69–1.0), and at 3 years (<i>N</i> = 56 and 51), 0.98 (0.49–1.0) and 0.99 (0.54–1.0). Over time, a statistically significant decrease in PDC was observed [<i>p</i> = 0.01 (ETI, years 1 vs. 3) and <i>p</i> = &lt; 0.01 (IVA)]. The percentage of non-adherent pwCF increased over time, from 3.6% (IVA) and 3.3% (ETI) at year 1 to 15.7% (IVA) and 12.5% (ETI) at year 3.</p> Conclusions <p>Three-year adherence to ETI and IVA based on pharmacy refill data was high, yet declined over time.</p>