Studies have shown a higher risk of hepatocellular carcinoma (HCC) with higher baseline serum hepatitis B virus (HBV) DNA levels in chronic hepatitis B (CHB) patients. However, the association between very high HBV DNA levels (>6 log₁₀ IU/mL) and HCC risk remains unclear, especially in middle‐aged and old HBeAg‐positive patients.

To identify the association between broad‐range HBV DNA levels and HCC risk.

We conducted a historical cohort study in Korea involving 6949 non‐cirrhotic, treatment‐naïve CHB patients with alanine aminotransferase (ALT) <2× upper limit of normal for >1 year. HBV DNA was >6 log₁₀ IU/mL in 2029 (29.2%) patients. Follow‐up was censored when the antiviral therapy was initiated.

The mean age of the patients was 45 years. During 8.0 years of median follow‐up, 363 patients (5.2%) developed HCC. By multivariable Cox regression analysis, HCC risk was highest with baseline HBV DNA levels of 6‐7 log₁₀ IU/mL (adjusted hazard ratio [aHR] 4.98; P < 0.001), and lowest with >8 log₁₀ IU/mL (aHR 0.90; P = 0.71) and ≤4 log₁₀ IU/mL (aHR 1.00; reference), which was independent of other predictive factors. The similar association between HBV DNA levels and HCC risk was consistently observed in all age subgroups (age <40, 40‐49 and ≥ 50 years).

HCC risk was highest with moderate serum HBV DNA levels of 6‐7 log₁₀ IU/mL in CHB patients without significant ALT elevation. Extending treatment indication to CHB patients with moderate levels of HBV DNA may be considered to further prevent HCC, regardless of ALT levels.