peer reviewed ; Introduction Nationwide studies comparing patients with hepatitis B and C virus (HBV and HCV) infections are mandatory for assessing changes in epidemiology. Aim The aim of this study was to compare epidemiological data and initial management of newly diagnosed patients with persistent HBV (HBsAg positive) or HCV (detectable HCV RNA) infection in Belgium. Patients and methods Data were extracted from two Belgian observational databases. Results A total of 655 patients (387 HBV and 268 HCV) were included. Compared with HCV patients, HBV patients were younger, more frequently men, more often of Asian or African origin (43 vs. 10%, P < 0.0001), and less frequently contaminated by transfusion or intravenous drug use (9 and 6% vs. 34 and 44%, P< 0.0001). Viral replication was assessed in 89% of HBV patients. Compared with HCV patients, HBV patients more frequently had normal alanine aminotransferase (ALT) levels (65 vs. 29%, P < 0.0001), less frequently underwent liver biopsy (29 vs. 67%, P < 0.0001), and were less often considered for antiviral therapy (25 vs. 54%, P < 0.0001). When taking only HBV patients with detectable viral replication into consideration, results remained unchanged. During the multivariate analysis, ALT was a major factor for performing liver biopsy or considering antiviral therapy in both groups. Conclusion HBV and HCV screening policies should be targeted toward immigrants and intravenous drug users, respectively. Guidelines recommending systematic search for viral replication should be reinforced in HBV patients. HBV patients less frequently underwent liver biopsy and were less often considered for antiviral therapy compared with HCV patients. Despite the lack of sensitivity and specificity, ALT remains a pivotal decision-making tool for liver biopsy and antiviral therapy in both infections.