We compared the efficacy of two polyenes, amphotericin B and natamycin, in two models of yeast infection. In one, treatment was begun immediately after inoculation, in the other it was delayed 24 hours. In each model infection withCandida albicanswas established in the corneal stroma of dutch-belted rabbits and treated topically with 5% natamycin or amphotericin B 0.15% and 0.075%. Quantitative isolate recovery techniques were used to assess response after 5 days of treatment. A significant therapeutic effect was present for amphotericin B in both models. However, delayed treatment with natamycin was ineffective using treatment schedules efficacious when begun 1 hour after inoculation. A therapeutic effect was present only with administration of the drug every 1/2 hr. This altered response may reflect a difference in susceptibility between different growth phases in yeasts.