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Background: Direct‐acting antiviral (DAA) therapies for hepatitis C virus infection (HCV) lead to excellent rates of sustained virological response (SVR). However, loss to follow‐up (LTFU) for SVR testing remains a challenge. We examine factors associated with LTFU in a real‐world setting. Methods: Adults who received DAA therapy for HCV in one of 26 centers across Australia during 2016–2021 were followed up for 2 years. Data sources included the patient medical records and the national Pharmaceutical and Medicare Benefits Schemes. Linkage to Medicare provided utilization data of other health‐care providers and re‐treatment with DAAs. LTFU was defined as no clinic attendance for SVR testing by at least 52 weeks after DAA treatment commencement. Multivariable logistic regression assessed factors associated with LTFU. Results: In 3619 patients included in the study (mean age 52.0 years; SD = 10.5), 33.6% had cirrhosis (69.4% Child–Pugh class B/C), and 19.3% had HCV treatment prior to the DAA era. Five hundred and fifteen patients (14.2%) were LTFU. HCV treatment initiation in 2017 or later (adj‐OR = 2.82, 95% confidence interval [CI] 2.25–3.54), younger age (adj‐OR = 2.63, 95% CI 1.80–3.84), Indigenous identification (adj‐OR = 1.99, 95% CI 1.23–3.21), current injection drug use or opioid replacement therapy (adj‐OR = 1.66, 95% CI 1.25–2.20), depression treatment (adj‐OR = 1.49, 95% CI 1.17–1.90), and male gender (adj‐OR = 1.31, 95% CI 1.04–1.66) were associated with LTFU. Conclusions: These findings stress the importance of strengthening the network of providers caring for patients with HCV. In particular, services targeting vulnerable groups of patients such as First Nations Peoples, youth health, and those with addiction and mental health disorders should be equipped to treat HCV. [ABSTRACT FROM AUTHOR]