OBJECTIVE To compare efficiency and tolerance between topical 0.5% cyclosporine A (CSA) and fluorometholone (FML) for subepithelial infiltrates (SEI) complicating epidemic keratoconjunctivitis. METHODS We conducted a prospective double-blind randomized study involving 72 eyes with SEI. Thirty-eight eyes were treated with topical FML (FML group) and 34 eyes with CSA 0.5% eye drops (CSA group). Treatment was considered successful in case of SEI reduction and visual acuity improvement. Tolerance was evaluated by Schirmer test value, burning on eye drops instillation, and conjunctival injection. RESULTS Baseline characteristics of both groups were similar (P > 0.05). After 3 months of the regimen, resolution of SEI was 3 times more observed in the FML group than that in the CSA group (P = 0.026). After 6 months, resolution of SEI was observed in 70% of the FML group and in 47% of the CSA group (P = 0.068). The recurrence of SEI was almost twice higher in the FML group than that in the CSA group (16% vs. 9%). FML was better tolerated during the first 3 months: a higher Schirmer test value (P = 0.0003), less burning on instillation (P = 0.242), and less conjunctival injection (P = 0.003). For the rest of the follow-up period, the 2 groups were comparable in tolerance. No ocular hypertension was noted. CONCLUSIONS Epidemic keratoconjunctivitis can evolve favorably under both FML and CSA. The effect of FML is faster and CSA is more durable with fewer recurrences. Both are safe therapeutic options for long-term control of SEI.