We treated a healthy soft contact lens wearer who developed Acanthamoeba sclerokeratitis in the left eye. The patient had severe pain and ring-shaped subepithelial infiltrates. The keratitis progressed and scleral nodules developed despite aggressive treatment with topical clotrimazole, dibromopropamidine isethionate, and corticosteroids. Corneal transplantation and cryotherapy were performed. The corneal button demonstrated Acanthamoeba cysts. Cultures of biopsy specimens taken from two different scleral nodules at two separate times were positive for Acanthamoeba. The disease progressed despite a second corneal graft and the addition of polyhexamethylene biguanide eyedrops. Enucleation of the left eye was required. Histopathologic examination of the specimen documented an Acanthamoeba cyst associated with a granulomatous inflammatory response deep in the sclera. Acanthamoeba scleritis may be associated with a poor prognosis, even with intensive medical and surgical treatment.