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Study Objectives To determine the incidence of hepatotoxicity in critically ill patients who were treated with voriconazole and to identify potential risk factors for voriconazole-associated hepatotoxicity in these patients. Design Single-center prospective observational study. Setting Intensive care unit ( ICU) in a university-affiliated hospital in Xi'an, China. Patients Sixty-three adults, admitted to the ICU between January 2010 and July 2015, who had an ICU length of stay longer than 3 days, had received voriconazole treatment for at least 3 days, and had at least one trough voriconazole plasma concentration ( VPC) measurement. Intervention All patients received CYP2C19 genotyping and were evaluated for the development of hepatotoxicity by assessing liver function tests performed before, during, and after voriconazole therapy. Measurements and Main Results Hepatotoxicity was classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events ( CTCAE) grade scores and was defined as a CTCAE grade score that had increased by at least 2 grade scores over the baseline score. Hepatotoxicity occurred in 12 (19%) of the 63 patients. Characteristics of the patients who developed hepatotoxicity were compared with those of the patients who did not develop hepatotoxicity by univariate and multivariate Cox regression analyses. In the univariate analysis, Acute Physiology and Chronic Health Evaluation II score, invasive fungal infection classification, CYP2C19 genotype, and trough VPC were identified as the variables, and they were subsequently combined in the multivariate regression analysis. Multivariate Cox regression analysis revealed that hepatotoxicity was independently associated with trough VPC (hazard ratio 1.76, p<0.001). The relationships between trough VPCs and probability of hepatotoxicity were explored by using logistic regression analysis, and a target VPC upper limit of 4 mg/L was identified. The Kaplan-Meier method for the cumulative incidence of hepatotoxicity showed a significant difference between patients with trough VPCs of 4 mg/L or higher and those with VPCs lower than 4 mg/L (p<0.001). Conclusion Trough VPC was an independent risk factor associated with a greater risk of developing hepatotoxicity in critically ill patients, with a potentially toxic target trough concentration threshold of 4 mg/L identified for this complex population. [ABSTRACT FROM AUTHOR]