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Summary: Background: It is unknown whether patients with chronic hepatitis B (CHB) who achieved hepatitis B surface antigen (HBsAg) seroclearance spontaneously or following anti‐viral therapy have similar clinical outcomes. Aim: To compare the risk of hepatocellular carcinoma (HCC) in patients with CHB who either cleared HBsAg spontaneously or following anti‐viral therapy Methods: Adult CHB‐monoinfected patients who cleared HBsAg between January 2000 and March 2019 were identified from a territory‐wide database in Hong Kong. Patients with liver transplantation and/or HCC before HBsAg loss were excluded. Patients' demographics, comorbidities, anti‐viral treatment, laboratory parameters and HCC development were analysed. Results: Of 7,124 identified patients with CHB who cleared HBsAg, mean age was 58.1 ± 13.8 years; 4,340 (60.9%) were male; 451 (6.3%) had cirrhosis; 5,917 (83.1%) and 1,207 (16.9%) had spontaneous and nucleos(t)ide analogue (NA)‐induced HBsAg seroclearance, respectively. Most patients had normal liver function at HBsAg loss. Patients with NA‐induced HBsAg seroclearance were younger, and more likely to be male and cirrhotic than patients with spontaneous HBsAg loss. At a median (interquartile range) follow‐up of 4.3 (2.2‐7.6) years, 97 (1.6%) and 16 (1.3%) patients with spontaneous and NA‐induced HBsAg loss developed HCC, respectively. Patients who achieved NA‐induced HBsAg loss had comparable HCC risk as those with spontaneous HBsAg loss (adjusted subdistribution hazard ratio 0.75, 95% CI 0.43‐1.32, P = 0.323). The results remained robust in propensity score weighting and matching analyses. Conclusion: The HCC risk was similarly low after either spontaneous or NA‐induced HBsAg seroclearance in a territory‐wide cohort of patients with CHB who had cleared HBsAg. [ABSTRACT FROM AUTHOR]