Background: About 40 to 50 percent of all instances of microbial keratitis are caused by fungal keratitis (FK). Untreated FK can lead to corneal damage and endophthalmitis, both of which can lead to irreversible vision loss. Since long-term consequences, including blindness, can be prevented by timely diagnoses and treatment of microbial keratitis, there is no laboratory support for this type of diagnosis. Some experts in the field of ophthalmology have long held that it is possible to discriminate between fungal and bacterial infections of the cornea using clinical indicators. The aim of the study: It was assessment of the efficacy and safety of topical and systemic and sub-conjunctival fluconazole treatment for refractory fungal keratitis. Patients and Methods: Eleven people with refractory fungal keratitis took part in this investigation. All cases were managed with topical fluconazole 2% hourly for 2 days, then tapered 5 times/day for one week, sub-conjunctival fluconazole 2mg/ml once for 14 days and oral fluconazole 150mg per week daily. The diagnosis was based on KOH wet mount and clinical signs of fungal keratitis. Result: The result was eight of patient successfully treated with visual acuity improvement and local nor systemic side effect were observed. Conclusion: Severe fungal keratitis can be treated with topical and systemic, sub-conjunctival fluconazole, which may reduce the need for surgical intervention.