BACKGROUND Posaconazole is superior to fluconazole or itraconazole in preventing invasive fungal diseases (IFDs) in patients with haematological malignancies; however, there have been reports of the comparing posaconazole and voriconazole. METHODS This single-centre, retrospective study in China enrolled AML, ALL and MDS patients, among others. Prophylaxis with posaconazole or voriconazole was administered for patients recovering from neutropenia or who had achieved complete remission. The primary emphasis was proven, probable, or possible IFDs during treatment. The cost-effectiveness, the proportion of adverse events and systemic antifungal treatment were the secondary emphasis. RESULTS A total of 164 patients were recruited to receive posaconazole (n=81) or voriconazole (n=83). The incidence rates of proven, probable or possible IFD were 2.46% (2/81) and 4.82% (4/83) in the posaconazole group and voriconazole groups, respectively (P>0.05). Only one patients experienced adverse events on posaconazole, while eleven patients experienced such events on voriconazole (P=0.003). Patients receiving posaconazole or voriconazole had similar proportions of systemic antifungal treatment: 18.52% (15/81) in the posaconazole group and 16.87% (14/83) in the voriconazole group (P>0.05). In the cost-effectiveness analysis, the prognosis of the two groups was close, but the drug acquisition costs of posaconazole were higher than those of voriconazole (P=0.021). CONCLUSIONS Posaconazole and voriconazole have the same prophylactic effect against IFDs in high-risk neutropenic Chinese patients. However, the safety of posaconazole is superior to that of voriconazole, while in terms of cost-effectiveness, voriconazole has an advantage over posaconazole.