BACKGROUND & AIMS: Patients with drug-induced liver injury (DILI) frequently have comorbid conditions, but the effects of non-liver comorbidities on outcomes are not well understood. We investigated the association between comorbidity burden and outcomes of patients with DILI, and developed and validated a model to calculate risk of death within 6 months. METHODS: A multiple logistic regression model identified variables independently associated with death within 6 months of presenting with suspected DILI (6-month mortality) for 306 patients enrolled in the Drug-Induced Liver Injury Network prospective study at Indiana University (discovery cohort). The model was validated using data from 247 patients with suspected DILI enrolled in the same study at the University of North Carolina (validation cohort). Medical comorbidity burden was calculated using the Charlson Comorbidity Index-patients with scores higher than 2 were considered to have significant comorbidities. RESULTS: Six-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. In the discovery cohort, significant comorbidities (odds ratio, 5.4; 95% confidence interval [CI], 2.1-13.8), Model for End-Stage Liver Disease score (odds ratio, 1.11; 95% CI, 1.04-1.17), and serum level of albumin at presentation (odds ratio, 0.39; 95% CI, 0.2-0.76) were independently associated with 6-month mortality. A model based on these 3 variables identified patients who died within 6 months, with c-statistic values of 0.89 (95% CI, 0.86-0.94) in the discovery cohort and 0.91 (95% CI, 0.83-0.99) in the validation cohort. We developed a web-based calculator for use in the clinic to determine risk of death within 6 months for patients with suspected DILI. CONCLUSIONS: We developed and validated a model based on comorbidity burden, Model for End-Stage Liver Disease score, and serum level of albumin that predicts 6-month mortality in patients with suspected DILI.