Between January 2002 and December 2003 all 157 patients (pts) that underwent lung transplantation (LTx) at our institution were prospectively screened for invasive aspergillosis (IA) during their perioperative hospital stay. Patients were regarded as IA positive, if they met the EORTC criteria for 'probable' or 'proven' IA. Records of pts were screened retrospectively for antimycotic prophylaxis. Eight of the 157 pts developed 'probable' or 'proven' IA (5.1%) within 17 +/- 10 days after LTx. This was associated with a 14-fold increased mortality compared with all pts without aspergillosis (P < 0.01, OR 13.8, CI(95%) 2.5-82). Preoperative colonization with Aspergillus was a significant risk factor for IA (P < 0.001, OR 21.9, CI(95%) 4.9-97). We switched our prophylactic strategies to the primary administration of voriconazole in high risk pts (pre-LTx colonization) starting in December 2002. Six pts (6%) of 101 pts receiving itraconazole for antimycotic prophylaxis beginning at postoperative day (POD) one developed IA, of which three pts showed cerebral aspergillosis. One pt (5%) of 18 pts receiving voriconazole prophylaxis developed IA, while 10 pts showed pretransplant colonization with Aspergillus species. Thirty-eight pts received itraconazole prophylaxis at a later time point (>POD 14). By switching our prophylactic strategy to the use of voriconazole in high risk pts, we have decreased the incidence of IA from 8% (six of 75) in 2002 to 2% (two of 82) in 2003. This study shows a high incidence of IA during the very early postoperative course after LTx of 5%. This is associated with a significantly increased risk for mortality. Voriconazole prophylaxis appears to be superior to itraconazole, especially in high risk pts with pretransplant Aspergillus colonization.