Sensitive polymerase chain reaction assays to measure hepatitis B virus (HBV) DNA became only available the last decade. Hence, the long‐term outcome of Caucasian patients in Western Europe with hepatitis B e antigen (HBeAg)‐negative chronic infection, especially with a baseline HBV DNA level ⩾2000 IU/mL, is still unclear. Out of a cohort of 1936 chronic HBV patients, 413 Caucasian individuals were identified with HBeAg‐negative chronic infection, defined as persistently normal alanine aminotransferase (ALT) levels and HBV DNA levels <20 000 IU/mL. During a mean follow‐up of 12 years, 366 (88.6%) maintained an HBeAg‐negative chronic infection status, whereas 25 (6.1%) developed chronic active hepatitis (CAH). In total, Nine of these 25 CAH cases were related to immunosuppression. In total, 22 (5.3%) individuals had ALT > 2 × upper limit of normal due to non‐HBV‐related causes. The cumulative probability of spontaneously developing CAH after 10 years was almost exclusively seen in patients with baseline HBV DNA level ⩾2000 IU/mL (11.7% vs 1.2%; P < .001). Advanced liver disease developed significantly more in patients with baseline HBV DNA level ⩾2000 IU/mL (5.2% vs 1.5%; P = .018) and occurred especially in patients with obesity (16.7% vs 4.2%; P = .049). The incidence of hepatocellular carcinoma was 0.0%. Caucasian patients with HBeAg‐negative chronic infection and baseline HBV DNA level <2000 IU/mL have an excellent long‐term prognosis in the absence of immunosuppressive therapy. However, patients with baseline HBV DNA level ⩾2000 IU/mL are at risk to develop advanced liver disease. Highlights This is the first long‐term study in Caucasian patients with HBeAg‐negative chronic infection making use of sensitive PCR assays. Patients with baseline HBV DNA levels >2000 IU/mL have a cumulative incidence of HBsAg loss of 10% over 10 years. Patients with baseline HBV DNA levels >2000 IU/mL have a favourable long‐term prognosis. Baseline HBV DNA level <2000 IU/mL is associated with a higher risk of advanced liver disease.