A 49-year-old woman underwent bilateral lung transplantation for advanced idiopathic pulmonary fibrosis. During the postoperative period she received immunosuppressive medications as well as corticosteroids. Aspergillus fumigatus grew from a sputum sample, and she was treated with nebulized amphotericin. She was discharged on tacrolimus and prednisone. After initially doing well, she required re-hospitalization for treatment of cytomegalovirus and Pseudomonas aeruginosa pneumonia. She was treated with ganciclovir and cefepime and, after a 2-week hospitalization, was discharged. Seven months after transplantation she developed progressive sinusitis, treated with antibiotics and sinus debridement surgery. Aspergillus organisms were recovered and, at the periphery of the tangled masses of Aspergillus hyphae, numerous amebic cysts were also identified, which were morphologically consistent with Acanthamoeba spp. Subsequent electron microscopy and immunofluorescent staining confirmed this impression. She was initially treated with intravenous amphotericin, later changed to voriconazole and caspofungin. Debridement of the sinuses 3 weeks later revealed fungal hyphae but no amebae. Infections with Acanthamoeba have rarely been reported in lung transplantation but have been recognized in bone-marrow and renal transplant patients, and have been lethal in many cases, particularly in patients with immunosuppression due to human immunodeficiency virus infection. More recently, aggressive antimicrobial therapy has resulted in successful outcomes, as discussed herein.