The objective of this study was to evaluate the association between the use of anti-tuberculosis (anti-TB) agents, isoniazid (INH), rifampicin (RIF), and their combination (INH + RIF), and the risk of hepatocellular carcinoma (HCC) in cirrhotic patients. This population-based case-control study was conducted using a research database of Taiwan's National Health Insurance program. Cirrhotic patients first diagnosed with HCC between 1996 and 2011 (n = 50,351), among whom 4,738 were anti-TB medication users, were evaluated. Cirrhotic patients who did not develop HCC within the same period, frequency-matched according to age, sex, and index year, were evaluated as the control group (n = 47,488). The adjusted odds ratio (OR) of HCC was 1.34 [95 % confidence interval (CI), 1.20-1.50] in INH + RIF users compared with non-INH + RIF users. Long-term (>12 months) use of INH, RIF, and INH + RIF was significantly associated with increased risk of HCC, with an adjusted OR of 3.51 (95 % CI, 2.11-5.84), 4.17 (95 % CI, 2.76-4.31), and 7.17 (95 % CI, 4.08-12.6), respectively, after adjusting for age, sex, and comorbidities. An average dose of INH + RIF >16,050 mg/year was associated with increased risk of HCC in cirrhotic patients, with an adjusted OR of 1.48 (95 % CI, 1.27-1.73). Our results indicate that cirrhotic patients with long-term or high-dose INH and RIF treatment, particularly their combination, are associated with increased risk of HCC development.