Abstract: Recently, concerns were raised of high rates of HCC recurrence in patients treated with direct acting antivirals (DAA) for hepatitis C infection. We investigated the HCC occurrence and recurrence rates within six months after treatment with DAA with or without Pegylated Interferon (PEG-IFN) in real life. This is a retrospective, multicenter cohort trial, executed in 15 hospitals distributed across Belgium. Populations were matched based on fibrosis score (Metavir F3-F4). Patients with a Child-Pugh score ≥ B were excluded. In total, 567 patients were included, of whom 77 were treated with PEG-IFN+DAA between 2008 and 2013 and 490 with DAA without PEG-IFN between 2013 and 2015. Patients treated with PEG-IFN+DAA (53±9y) were younger than patients treated with DAA without PEG-IFN (59±12y) (p=0.001). 47% of patients treated with PEG-IFN+DAA were in the F4 stage versus 67% of patients treated with DAA without PEG-IFN (p=0.001). Screening was inadequate in 20% of both patient groups (p=0.664). The early occurrence rate of HCC was 1.7% and 1.1% in patients treated with DAA with and without PEG-IFN respectively (p=0.540). The early recurrence rate was 0% in patients treated with PEG-IFN+DAA, and 15.0% in patients treated with DAA without PEG-IFN (p=0.857). There is no difference in early occurrence of new HCC between patients treated with DAA with and without PEG-IFN. We did observe a high early recurrence rate of HCC in patients treated with DAA without PEG-IFN. However, these patients were at baseline more at risk for HCC. Finally, in 20% screening for HCC was inadequate.