The incidence of and risk factors associated with hepatotoxicity in patients with chronic hepatitis have not been systematically studied. Therefore, we conducted a prospective study that included former drug users who were treated with isoniazid for latent tuberculosis infection. Of 415 patients, 20 (4.8%; 95% confidence interval [CI], 3-7.4) had hepatotoxicity diagnosed, and 6 (1.4%; 95% CI, 0.5-3.2) developed clinical hepatitis, none of whom had serious symptoms. The only 2 factors independently associated with isoniazid hepatotoxicity were excessive alcohol consumption (odds ratio [OR]; 4.2, 95% CI, 1.6-10.8; P=.002) and a high baseline alanine transaminase level (OR, 4.3; 95% CI, 1.6-11.4; P=.002). The presence of hepatitis C virus antibodies was associated with hepatotoxicity only on univariate analysis. Treatment with isoniazid in drug users appears to be safe and well tolerated, although frequent asymptomatic elevations in transaminase levels were observed.