Invasive aspergillosis caused by medical triazole-resistant Aspergillus fumigatus is described in two patients. A 31-year-old male with chronic granulomatous disease developed pulmonary aspergillosis despite itraconazole prophylaxis. A. fumigatus was cultured from the lung and was found to be azole-resistant. The patient was successfully treated with caspofungin. The second patient was a 13-year-old boy with acute lymphoid leukaemia. He developed pulmonary aspergillosis that failed to respond to voriconazole therapy. The infection spread to the brain and an azole-resistant isolate was cultured from a lung biopsy. Despite a switch to liposomal amphotericin B in combination with caspofungin, the infection progressed and the patient died. Azole-resistance has emerged in A. fumigatus and may develop through the treatment of patients. However, there is evidence that in the Netherlands, resistance might be emerging through fungal exposure to azole fungicides. Azole resistance further complicates the management of invasive aspergillosis and should be considered as cause for treatment failure.