Purpose: To investigate the inciting agent, clinical features, and the efficacy of hourly steroids in the prophylaxis in a diffuse lamellar keratitis (DLK) epidemic. Methods: One hundred and five eyes of 58 patients that had DLK after LASIK were included in the study. To identify the cause of the epidemic, some interventions were made: irrigation solution was changed from BSS to Ringer lactate (week 5), wiping of the interface with a sponge was discontinued (week 6), the air conditioner in the LASIK room was checked (week 6), the routine postoperative topical regimen was changed from fluoromethalone and fluoroquinolones 4 times a day to hourly prednisolone acetate or dexamethasone sodium and fluoroquinolones (week 7), and the trademark of the drape used was changed (week 12). Results: There was no statistical difference in any of the attack rates associated with variables including BSS versus Ringer lactate (9.9 vs. 14%, p=0.4), and air conditioner check with wiping versus not wiping the interface with the microsurgical sponge (14.0 vs. 18.2%, p=0.6). There was a significant decrease in the attack rate from 18.2 to 5.3% with use of the hourly prophylactic topical steroids (p=0.012). After introduction of a new trademark of the drape, the incidence of DLK was further reduced from 5.3 to 0.7% (p=0.016). Conclusion: The cause in a particular DLK epidemic should be identified and eliminated adopting a scientific approach. Hourly steroid use for prophylaxis is recommended until the etiologic agent responsible has been identified. Copyright (C) 2004 S. Karger AG, Basel.