OBJECTIVE To identify risk factors at diagnosis that can serve as prognostic indicators of primary treatment failure in cases of fungal keratitis. METHODS Prospective, nonrandomized, interventional, comparative study. METHODS A total of 115 consecutive patients with fungal keratitis treated at one center during a 6-month period. METHODS Patients with a microscopic corneal ulcer smear that was positive for fungus were enrolled and treated with 5% natamycin monotherapy according to the protocol of the hospital. Treatment responses were assessed at the end of 4 weeks. The prognostic indicators were used in a Poisson model for multiple regression analysis to estimate the relative risk of the main prognostic variables. METHODS Response of the ulcer to treatment. RESULTS Of the 115 patients analyzed in the study, 52 (45.2%) were treatment successes, 27 (23.5%) had slow-healing ulcers, and 36 (31.3%) were refractory to primary treatment. Multivariate analysis showed that the predictors of treatment failure were ulcers that exceeded 14 mm(2) (P = 0.009), the presence of hypopyon (P = 0.003), and identification of Aspergillus (P = 0.003). CONCLUSIONS In patients with fungal keratitis treated with 5% natamycin monotherapy, larger ulcer size and infection with Aspergillus were predictors of a poor outcome.