Aim: Hepatitis C virus (HCV) is the leading cause of hepatocellular carcinoma (HCC) in the United States. Achieving sustained viral response with interferon (IFN) treatment reduces the risk from 3％-5％ to 0.5％-1％ annually. Several studies reported unexpectedly high rates of HCC after treatment with direct-acting antivirals (DAAs). The aim of our study was to compare HCC rates in DAA-, IFN-treated and untreated populations. Methods: A literature search was conducted using ScienceDirect, Ovid?, Web of Science and MEDLINE through January 2019. Studies were included if they measured rates of de novo or recurrent HCC (following curative treatment) in HCV-infected persons. We included 138 studies (n = 177,512). Simple pooling of data and meta-analysis were performed, using the random effects method. Results: Mean age was higher in the DAA-treated vs. IFN-treated group (58.4 years vs. 52.6 years; P = 0.0073), as were diabetes prevalence (34.5％ vs. 11.7％; P ≤ 0.001) and incident cirrhosis (47.8％ vs. 34.2％, P = 0.0017). The incidence rate of de novo HCC was 2.01/100 person-years (py) (95％CI: 1.38, 2.67) in the DAA group and 1.45/100py (95％CI: 0.98, 1.94) in the IFN-treated group. HCC recurred at 16.76/100py (95％CI: 10.75, 22.91) in the DAA-treated group vs. 20.04/100py (95％CI: 2.58, 45.21) after IFN. After adjusting for factors such as age and cirrhosis, the hazard ratio was 0.58 (95％CI: 0.20, 1.07) for HCC occurrence and 0.59 (95％CI: 0.24, 1.03) for HCC recurrence after DAA treatment compared to IFN-based treatment.Conclusion: We did not find evidence for increased rates of HCC in DAA-treated compared with IFN-treated patients. Compared to those treated with IFN, older patients with additional risk factors for HCC were treated with DAAs. This imbalance appears to explain the higher numerical incidence of HCC among DAA-treated patients.