The aim of the study was to assess the long-term outcome of chronic hepatitis B surface antigen (HBsAg) carriers in the general population in North Greece (Thrace), an area with an intermediate endemicity. This was a part of the Interreg I-II EC project. Two hundred sixty three chronic HBsAg(+) carriers, median age 34 years (20–65), were evaluated prospectively for a median follow-up of 5 years (2–12). Hepatitis B virus (HBV) markers and ALT were examined every 6 months and serum HBV-DNA every 12 months. Liver biopsy was undertaken at presentation and every 2–4 years. Fourteen of 263 (5.3%) subjects were HBeAg(+) and 249/263 (94.7%) HBeAg(−)/anti-HBe(+) of whom 48 (19.3%) had elevated ALT, and HBV-DNA levels ranging from 1.4 × 105–4 × 107 copies/ml. Inactive carriers (98/195 (50.3%)) had detectable HBV-DNA (median 2.6 × 103 range 0.042 × 104–1.9 × 104 copies/ml); 4/195 (2%) exhibited HBV reactivation during the observation period (all had HBV-DNA >104 copies/ml at presentation). Patients (7/14 (50%) HBeAg(+)) developed anti-HBe(+), annual rate 10%. Subjects (16/195 (8%)) lost HBsAg, all were inactive carriers; 10 developed anti-HBs (annual rate 1%). Liver biopsy was normal or with minimal changes in 92/95 (97%) inactive carriers and remained so at 4 years follow-up. In contrast, 4/48 (8.3%) HBeAg(−)/anti-HBe(+) patients with active disease had deterioration of liver histology. In this cohort study: (a) the annual seroconversion rate was 1% for the HBsAg and 10% for the HBeAg, (b) 23.6% of the HBsAg(+) carriers had active liver disease and 39% moderate fibrosis at presentation of whom a small proportion deteriorated over the observation period, (c) HBsAg carriers with HBV-DNA level <104 copies/ml had persistently normal ALT and unchanged liver histology over the follow-up period of up to 12 years. J. Med. Virol. 77:173–179, 2005. © 2005 Wiley-Liss, Inc.