We describe six inpatients with acute non-lymphocytic leukaemia who developed invasive infection with Scedosporium prolificans resistant to amphotericin B, flucytosine, ketoconazole, fluconazole, and itraconazole. All six patients died. Phenotypic and genotypic assessment of samples from clinical material and ambient air from the isolation rooms where the patients were being treated showed that the epidemic was caused by a single strain. After implementation of aerial control measures, there were no further infections with this organism. We conclude that fatal multidrug-resistant S prolificans epidemics can be aerially transmitted and can be prevented with implementation of appropriate infection-control measures.