OBJECTIVES: To quantify the incidence of hepatotoxicity associated with antithyroid drugs and analyze the relative hepatotoxicity risk of methimazole (MMI) and carbimazole (CBM) compared to propylthiouracil (PTU) among patients with hyperthyroidism. METHODS: A retrospective population-based cohort study was conducted by analyzing data from the Taiwan National Health Insurance Research Databases between January 1, 2004 and December 31, 2008. Patients diagnosed with hyperthyroidism (ICD-9-CM codes 242.xx, 775.3) and initially receiving antithyroid drugs were identified as the study cohort, in which MMI/CBM and PTU users were further specified. The two groups were followed up to observe the occurrence of hepatotoxic events, including jaundice, cholestasis, noninfectious hepatitis, acute liver failure, and liver transplant. Crude incidence rates of the hepatotoxicity per 1000 person-years were calculated. Cox proportional hazard models were employed to estimate crude and adjusted hazard ratios (HRs) of hepatotoxicity risks for MMI/CBM relative to PTU. RESULTS: The study cohort comprised a total of 71,379 patients with hyperthyroidism. The hepatitis outcome was observed to have the highest incidence in both MMI/CBM and PTU users, with a rate of 11.44 and 9.89 events per 1000 person-years, respectively. The comparative risk analyses indicated that use of MMI/CBM exerted a significantly increased risk of hepatitis than use of PTU (adjusted HR, 1.23; 95% CI, 1.03-1.47). Additionally, MMI/CBM prescribed at an average daily dose greater than 10 mg further enhanced the risk of jaundice (adjusted HR, 1.99; 95% CI, 1.13-3.49) and hepatitis (adjusted HR, 2.33; 95% CI, 1.93-2.82) to a larger degree than any use of PTU. CONCLUSIONS: Hepatitis is the most frequently occurring hepatotoxicity outcome for both MMI/CBM and PTU users. Notably, MMI/CBM is associated with a higher risk of hepatitis than PTU in a dose-dependent manner. Health care professionals should be vigilant to the symptoms of hepatitis for patients prescribed antithyroid drugs, especially for those receiving higher doses of MMI/CBM.