Background <p>Isavuconazole is a recent broad-spectrum triazole indicated for the treatment of invasive aspergillosis and mucormycosis when amphotericin B is inappropriate. However, limited information exists on its clinical use.</p> Objective <p>We set up a retrospective multicentre study to describe the clinical practice of isavuconazole including indications, exposure, and hepatic safety.</p> Methods <p>From January 2021 to June 2023, all patients who received isavuconazole and had at least one therapeutic drug monitoring (TDM) measurement, were included. To identify independent predictors of isavuconazole trough concentrations (<i>C</i>_min), linear regression analyses were performed. Causal relationship between the occurrence of liver injury and isavuconazole was also analysed.</p> Results <p>Most of the included patients (<i>n</i> = 102) were admitted into haematology units (41.1% [<i>n</i> = 42]) or intensive care units (ICU) (30.4% [<i>n</i> = 31]). Aspergillosis (47.0% [<i>n</i> = 48]), mucormycosis (25.6% [<i>n</i> = 26]), and off-label empirical treatments (18.6% [<i>n</i> = 19]), were the three most common indications. About half of the patients (46.1% [<i>n</i> = 47]) had an optimal exposure, while 42.2% (<i>n</i> = 43) were underexposed, and 11.7% (<i>n</i> = 12) were overexposed. Albumin level on the day of TDM was a significant factor associated with an increase in isavuconazole <i>C</i>_min (<i>p</i> = 0.010). Among the 11 patients who had liver test abnormalities, isavuconazole was discontinued in six (<i>n</i> = 6) patients and liver injury was attributable to isavuconazole in two (<i>n</i> = 2) patients.</p> Conclusions <p>This multicentre analysis highlighted the common use of isavuconazole as an off-label indication, as well as the frequent underexposure of patients to isavuconazole. Albumin on the day of TDM appeared to be an important factor driving isavuconazole exposure, especially in ICU patients.</p>