PURPOSE: To report a case of successful medical treatment with oral posaconazole in refractory fungal keratitis caused by Paecilomyces lilacinus. METHODS: Case report. RESULTS: A 57-year-old male, soft contact lens wearer presented with irritation, pain, photophobia, and reduced vision. Slit-lamp examination showed a large corneal epithelial defect with a peripheral infiltrate. The patient did not improve on fortified topical antibiotics. After the diagnosis of P. lilacinus fungal keratitis, oral voriconazole and topical antifungal therapy were started. Despite antifungal therapy, progressive disease required therapeutic penetrating keratoplasty. Postoperatively, because of clinical signs of recurrence and in vivo confocal microscopy findings of presumed hyphae in the cornea, intracameral miconazole was injected and oral posaconazole was started. The patient improved and demonstrated no hyphae 6 weeks after starting posaconazole. When posaconazole was stopped, the cornea remained clear with excellent acuity. However, because of acute graft rejection 2 months after stopping posaconazole, keratoprosthesis was implanted, with no evidence of infection at surgery or during the 3.5-year follow-up. CONCLUSIONS: To the best of our knowledge, this is the first report on the use of oral posaconazole for Paecilomyces keratitis. Posaconazole might be indicated in the treatment of refractory Paecilomyces keratitis that is resistant to conventional therapy.