The resistance of Aspergillus fumigatus to azole is a hot topic because of its frequent environmental origin and its impact in the treatment of fungal infections. Two resistance mechanisms associated with this environmental origin of resistance: mutations TR34 / TR46 and L98H / Y121F / T289A. So far the TR46 / Y121F / T289A strains have been described in four European countries (Netherlands, Belgium, Germany and Denmark) and more recently in Asia and Africa. Here we report the isolation of a TR46 / Y121F / T289A strain in France. This is a patient of 23 years, and cystic fibrosis followed at Rouen University Hospital. In March 2014, mycological analysis of sputum carried out systematic way revealed the presence of A . Fumigatus . As part of the monitoring of resistance to azoles, the Antifungal Etest® highlighted high-level resistance to voriconazole (MIC> 32μg / mL) but more moderate itraconazole and posaconazole, data confirmed for both first antifungal by EUCAST reference technique. Molecular analysis of the gene cyp51A and its promoter highlighted the mutation TR46 / Y121F / T289A. A retrospective analysis of 13 A . fumigatus isolated in this patient since 2007 could detect, in February 2013, another isolate resistant to voriconazole also carry the mutation TR46 / Y121F / T289A. An environmental study failed to find stem TR46 / Y121F / T289A in the immediate vicinity of the patient (non-residential). Exposure during business trips in the Netherlands in November 2012 and July 2013, where stem TR46 / Y121F / T289A were isolated in 2009, may be considered. Nevertheless contamination in France can not be excluded, strains carrying the signature TR46 / Y121F / T289A has been recently identified by our team in this region (unpublished personal data). These resistant strains are linked to therapeutic failures voriconazole, the determination of the in vitro susceptibility of A. fumigatus to antifungal agents should be routinely performed in cases of treatment with azoles.