A 62-year-old lung transplant recipient had Fusarium proliferatum pneumonia during itraconazole prophylaxis. Severe dyspnea and emphysema ensued, requiring supplemental oxygen therapy. Therapeutic options for this patient were limited; renal insufficiency and cyclosporine use precluded amphotericin B therapy, and susceptibility testing indicated that itraconazole and fluconazole had poor activity against F proliferatum. Treatment with posaconazole, a new triazole in clinical development for the prophylaxis and treatment of fungal infection, resulted in rapid clinical improvement and successful eradication of F proliferatum. Posaconazole may provide effective treatment for difficult-to-treat Fusarium infections.