OBJECTIVES: No randomised controlled trial has compared voriconazole and posaconazole directly for prophylaxis against invasive fungal infections (IFI) in high risk haematology patients. We performed a systematic review and indirect comparison of voriconazole versus posaconazole using itraconazole/fluconazole as the common comparator. METHODS: Systematic review of full body of evidence including randomised controlled trials and non-randomised studies. Adjusted indirect meta-analysis was performed using Bucher method. Non-randomised studies provide evidence for direct comparison between voriconazole and posaconazole. RESULTS: A total of 4 RCTs and 4 non-randomised studies that evaluated voriconazole or posaconazole were included. In these studies, two risk groups were identified on the basis of disease type – the haemopoetic stem cell transplant (HSCT) at risk of GVHD population, and acute myelogenous leukaemia or myelodysplastic syndrome (AML/MDS) population. The indirect estimates of risk differences (RD) were not statistically significantly different from 0.0; therefore indicating that voriconazole is not worse than posaconazole in terms of the incidence of proven or probable IFI [RD (95% CI): 0.00 (-0.06, 0.06) in HSCT/GVHD; 0.04 (-0.06, 0.14) in AML/MDS] and all-cause mortality rates [RD (95% CI): -0.00 (-0.07, 0.06) in HSCT/GVHD; 0.03 (-0.09, 0.16) in AML/MDS]. Results should be interpreted with caution due to heterogeneity between the risk levels of patient populations. However, the robustness of the indirect comparisons can be supported by the four direct non-randomised studies which consistently demonstrated similar efficacy of voriconazole and posaconazole and superior efficacy of voriconazole over itraconazole and fluconazole based on the incidence of breakthrough IFI. CONCLUSIONS: The clinical evidence presented in the direct and indirect comparisons consistently demonstrate that there are no statistically significant differences between voriconazole and posaconazole in terms of efficacy outcomes. Voriconazole offers an alternative option to posaconazole, which is the only therapy currently reimbursed on the Australian Pharmaceutical Benefits Schedule for prophylaxis of IFI.