OBJECTIVES: To describe direct medical costs and factors associated with three disease stages of chronic hepatitis B virus infection (CHB) in Guangzhou, China. METHODS: We conducted a retrospective cohort study of patients with CHB using a hospital information system database from 2008 to 2012 in the largest specialized infection hospital in Guangdong Province, China. Average annual costs and cost components were calculated. Generalized estimating equations were applied to explore associations between factors and costs. All costs were adjusted to RMB in 2012 at a discounting rate of 5% per year. RESULTS: A total of 65,792 (58 455 outpatients and 7 337 inpatients) were involved in the analysis. Number of visits/admissions (mean) per case per year for outpatient and inpatient were as follows: CHB: 4.56/1.12; Cirrhosis: 4.34/1.24; HCC: 2.46/1.13; and the corresponding average costs per person-time were: CHB: 581.79 and 8994.90 RMB; Cirrhosis: 670.71 and 16574.44 RMB; HCC: 643.69 and 20900.89 RMB, respectively. Antiviral (47.93%) and non-antiviral medicines (34.44%, including 16.99% of liver protectors and 6.31% of traditional Chinese medicine) for outpatient were the main cost components. Inpatient non-antiviral medicine and lab test contributed 45.56% and 23.38% of total costs; but antiviral medicine was only at 6.28% of total costs. Male, elder, antiviral patients, cirrhosis and HCC patients had statistically significant higher costs as compared with female, younger, non-antiviral and CHB patients. Among the outpatients, self-payment patients’ costs were the highest, followed by patients with medical insurance and free medical service, whereas opposite effect direction on costs was found in inpatients, and the differences were statistically significant. CONCLUSIONS: Direct medical costs of inpatients with CHB increase significantly as the disease progresses. Payment mode has different effect direction between outpatient and inpatient, indicating that reimbursement policy for clinic and hospitalized patients have an important role on direct medical costs in treating HBV.