To report a case of multidrug-resistant Fusarium sp keratitis that progressed to endophthalmitis and that eventually required enucleation. Case report and literature review. Isolate identification and susceptibility testing were performed by the Fungus Testing Laboratory at San Antonio, TX. A 52-year-old soft contact lens wearer had a corneal abrasion and developed a corneal infiltrate. Examination of corneal scrapings revealed filamentous hyphae with septation and conidia. Despite aggressive antifungal therapy with topical natamycin, amphotericin B, and systemic fluconazole, the keratitis progressed, and a penetrating keratoplasty was performed. Histopathologic analysis of the corneal button showed disruption of Descemet's membrane with periodic acid-Schiff-positive fungal hyphae on both sides. Recurrent infection of the graft and progression to endophthalmitis was treated with repeated intravitreal amphotericin B injections, repeat penetrating keratoplasties, and pars plana vitrectomies. Even after systemic use of itraconazole, voriconazole, and posaconazole and topical use of voriconazole, the infection progressed and an enucleation was required. Isolate identification and susceptibility testing found a multidrug-resistant Fusarium solani species complex, partially sensitive to natamycin only. Multidrug-resistant Fusarium sp is rare and may have devastating consequences in patients with advanced keratitis progressing to endophthalmitis. Such an extensive multidrug resistance is surprising in that resistance to antifungal treatment is supposedly rare. Empirical antifungal therapy is usually instituted using one or more antifungal agents, without checking antifungal sensitivities. In light of the growing concern for increased emergence of resistant strains, we propose a lower threshold to check for sensitivities in the face of unresponsive fungal infections.