Two patients admitted to two different medical wards of our institution following respiratory decompensation of chronic obstructive pulmonary disease (COPD) were subsequently transferred to the same room of the medical intensive care unit (ICU) and intubated. Both patients developed invasive pulmonary aspergillosis and died soon after. Because COPD itself is rarely associated with lethal pulmonary aspergillosis, both cases were reviewed, and a retrospective investigation was conducted. Both patients had repeated sputum cultures while on the medical ward before their admission to the ICU; none of the sample grew Aspergillus spp. A. fumigatus was found in tracheal aspirates of both patients from the first day of their intubation while in the ICU. The pulmonary condition of both patients worsened, and invasive aspergillosis was diagnosed by bronchoalveolar lavage. Despite therapy with amphotericin B, the patients died 16 and 22 d after intubation, respectively. Both deaths were attributed to pulmonary aspergillosis; autopsy confirmed a massive pneumonia of the five lobes due to A. fumigatus in one patient. Investigation revealed that an air filter had been replaced 30 h before the first patient was admitted to the room. Experimental air filter replacement performed 12 d after the second patient died revealed the presence of A. fumigatus on the surface of the filters as well as a 10-fold increase in room air fungal counts during the procedure. This study shows that exposure to high concentrations of airborne Aspergillus spp. related to air filter change was associated with fatal invasive aspergillosis in two mechanically ventilated patients. Such infection can be prevented by the establishment and application of guidelines for air filter replacement.