Two long-term therapy trials with high concentrations of antibiotic were carried out to determine the duration of therapy required to achieve bacteriologic cure of experimental Pseudomonas keratitis in guinea pigs. In the first study, corneas still contained Pseudomonas after 4 days of continual topical therapy with either tobramycin 400 mg/ml, amikacin 250 mg/ml, ticarcillin 400 mg/ml, or carbenicillin 400 mg/ml. In an 11-day trial of topical therapy with tobramycin 20 mg/ml, 34 of 36 corneas grew no Pseudomonas after 6 or more days of therapy. The bacteriologic response to therapy in this model occurred in two phases. About 99.9% or more of the organisms in the cornea were killed in the first 24 hr of therapy. The numbers of bacteria remaining in the cornea declined gradually over the next several days until the corneas were sterile. Optimal antibiotic therapy may include two stages: initial intensive therapy with high concentrations of antibiotic applied frequently to achieve a large rapid decrease in numbers of organisms in the cornea, followed by prolonged, less intensive therapy to eradicate organisms and prevent relapse.