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Background: Severe liver injury has been attributed to preventive treatment of latent tuberculosis infection with a 2-month course of rifampin-pyrazinamide., Methods: A retrospective cohort study in The Netherlands compared the hepatotoxicity of preventive treatment with rifampin-pyrazinamide with that of preventive treatment with isoniazid, and also with that of treatment for active tuberculosis containing at least isoniazid, rifampin, and pyrazinamide., Results: Preventive treatment with rifampin-pyrazinamide caused severe hepatotoxicity more often than did preventive treatment with isoniazid (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.26-5.39; P=.012), especially in patients <25 years old. It also caused severe hepatotoxicity more often than triple- or quadruple-drug tuberculosis treatment (OR, 2.61; 95% CI, 1.21-5.59; P=.016), especially if the pyrazinamide dose was > or =30 mg/kg. Preventive treatment with rifampin-pyrazinamide was more hepatotoxic even when the advised pyrazinamide dose of up to 20 mg/kg for preventive treatment was compared with the pyrazinamide dose of 30 mg/kg for tuberculosis treatment., Conclusions: Preventive treatment with rifampin-pyrazinamide causes severe hepatotoxicity more often than does preventive treatment with isoniazid or curative treatment for tuberculosis.