Objective: To evaluate the most effective intravitreal antibiotic treatment of vancomycin-sensitive and -resistant Enterococcus faecalis endophthalmitis. Design: Animal experiment. Setting: Seventy-eight New Zealand white rabbits received an intravitreal injection of 10(5) vancomycin-sensitive or -resistant E faecalis organisms in one eye. Infections were allowed to proceed 3 hours before dividing animals randomly into the following treatment groups (n=6, each): the vancomycin-sensitive E faecalis model-(1) vancomycin (1 mg/0.1 mL), (2) combined vancomycin (1 mg/0.1 mL) and amikacin (0.4 mg/ 0.1 mL), (3) combined vancomycin (1 mg/0.1 mL) and gentamicin (0.1 mg/0.1 mL), (4) combined vancomycin (1 mg/0.1 mL) and ceftazidime (2 mg/0.1 mt), (5) combined ampicillin (5 mg/0.1 mL) and gentamicin (0.1 mg/ 0.1 mL), and (6) pristinamycin (1 mg/0.1 mL); and the vancomycin-resistant E faecalis model-(1) same as above, excluding group 4. Control groups received sterile balanced salt solution. Twenty-four hours following intravitreal treatment, vitreous humor was collected for quantitative bacteriological studies. Results: Intravitreal therapy with combined vancomycin and amikacin provided the most effective reduction of vancomycin-sensitive E faecalis organisms compared with combined vancomycin and gentamicin therapy (P=.10, Wilcoxon's rank sum test) or any other treatment group (P<.01, Wilcoxon's rank sum test). For vancomycin-resistant E faecalis endophthalmitis model, the combined ampicillin and gentamicin therapy was the most effective, followed by the combined vancomycin and amikacin therapy (P<.01, Wilcoxon's rank sum test). Conclusions: Treatment with intravitreal vancomycin plus amikacin and with intravitreal ampicillin plus gentamicin provide an effective bactericidal therapy for severe experimental vancomycin-sensitive and -resistant E faecalis endophthalmitis, respectively.