<p>Voriconazole-associated liver injury has emerged as a critical factor driving its early discontinuation in clinical practice. However, reliable plasma biomarkers for detecting voriconazole-induced hepatotoxicity remain lacking. Metallothionein 1 (MT1) has been proposed as a potential biomarker for liver injury. This study aimed to investigate the role of circulating MT1 in voriconazole-associated hepatotoxicity. Tandem Mass Tag (TMT) quantitative proteomic analysis was employed to identify potential differential proteins. The circulating MT1 levels were measured in the plasmas of patients undergoing voriconazole therapeutic drug monitoring. TMT quantitative proteomic analysis revealed that MT1 was significantly upregulated in patients with voriconazole-induced liver injury. A total of 252 patients were enrolled in this study. Plasma MT1 levels were positively correlated with the liver function indices alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (γ-GT) levels. These levels significantly increased in patients with grade 1 or higher adverse events of ALT, AST, and γ-GT. Additionally, plasma MT1 levels were negatively correlated with procalcitonin and interleukin (IL)-6 levels. Moreover, plasma MT1 levels were negatively correlated with voriconazole trough concentration (C₀). When voriconazole C₀ &gt; 5.0&#xa0;μg/mL, MT1 levels decreased remarkably. The receiver operating characteristic curve analysis indicated that when the circulating MT1 level exceeded 17.4&#xa0;ng/mL, the likelihood of grade 1 or higher adverse events of ALT, AST, and γ-GT increased. Circulating MT1 may serve as a potential predictor of voriconazole-associated hepatotoxicity, aiding in the clinical assessment of such hepatotoxicity and providing a basis for reducing related adverse events.</p>