Voriconazole is the therapy of choice for aspergillosis. However, hepatotoxicity is the most common reason for the discontinuation of voriconazole. In contrast, posaconazole is well tolerated, with a low incidence of hepatotoxicity. In most cases, hepatotoxicity is associated with high voriconazole trough concentration influenced mainly by cytochrome P450 (CYP) 2C19 gene polymorphism. Compared with normal metabolizers, intermediate and poor metabolizers generally have higher voriconazole trough concentrations with an increased risk of hepatotoxicity. Here, we describe changes in hepatotoxicity throughout azole therapy in a patient with pulmonary aspergillosis (PA). Nevertheless, the patient with the normal metabolism genotype of CYP2C19 developed severe hepatotoxicity caused by voriconazole but tolerated posaconazole well, with a lack of direct cross-hepatotoxicity between the both. Interestingly, the patient had a high risk of hepatotoxicity at a low voriconazole trough concentration. Fortunately, elevated liver enzymes declined to the baselines with posaconazole treatment.