Invasive fungal infections (IFI) are common after lung transplantation and there are limited data for the use of antifungal prophylaxis in these patients. Our aim was to compare the safety and describe the effectiveness of universal prophylaxis with two azole regimens in lung transplant recipients. This is a retrospective study in lung transplant recipients from July 2003 to July 2006 who received antifungal prophylaxis with itraconazole or voriconazole plus inhaled amphotericin B to compare the incidence of hepatotoxicity. Secondary outcomes include describing the incidence of IFI, clinical outcomes after IFI and mortality. Sixty-seven consecutive lung transplants received antifungal prophylaxis, 32 itraconazole and 35 voriconazole and inhaled amphotericin B. There were no significant differences between groups in the acute physiology and chronic health evaluation (APACHE) score at the time of transplantation, demographic characteristics, comorbidities and concomitant use of hepatotoxic medications. Hepatotoxicity occurred in 12 patients receiving voriconazole and inhaled amphotericin B and in no patients receiving itraconazole (p < 0.001). There was no significant difference between groups with regard to the percentage of transplants with IFI, but one case of zygomycosis occurred in a transplant treated with voriconazole. Voriconazole prophylaxis after lung transplantation was associated with a higher incidence of hepatotoxicity and similar clinical effectiveness when compared to itraconazole.