Background: Hepatotoxicity associated with isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) has not been well studied in severely immunosuppressed people with HIV. Our objective was to determine risk factors for hepatotoxicity in severely immunosuppressed individuals taking IPT and ART. Setting: Multicenter study in resource-limited settings with high burden of tuberculosis. Methods: We conducted a secondary analysis of data from 1 randomized arm of the REMEMBER trial. The analysis includes participants with pre-ART CD4 cell counts of <50 cells/μL receiving IPT and ART for 24 weeks. Hepatotoxicity was defined as elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 × upper limit of normal or symptomatic hepatitis during IPT and ART. Logistic regression was used to identify baseline risk factors for hepatotoxicity. Time to occurrence of hepatotoxicity was estimated by the Kaplan-Meier method. Results: Among 426 participants (53% male, median age 35 years, median CD4 count 19 cells/µL), 31 developed hepatotoxicity (7.3%). Raised pretreatment AST/ALT (odds ratio [OR] 3.6, 95% confidence interval [CI]: 1.7 to 7.7) and hepatitis B surface antigen (HBsAg) seropositivity at baseline (OR 4.7, 95% CI: 1.7 to 12.9) were significantly associated with an increased risk of developing hepatotoxicity. Participants with both raised AST/ALT and positive HBsAg had a higher risk (OR 19.9, 95% CI: 5.3 to 74.3) and earlier onset of hepatotoxicity than participants who did not have these conditions at baseline. Conclusions: The incidence of hepatotoxicity during IPT and ART was high. Severely immunosuppressed individuals with raised pretreatment AST/ALT or HBsAg seropositivity need closer monitoring for hepatotoxicity.