Background: To investigate the efficacy of intravitreal piperacillin/tazobactam in rabbit eyes with experimental S. epidermidis endophthalmitis and to compare the outcomes with intravitreal vancomycin application. Material and Methods: Twenty-four New Zealand white albino rabbits were divided into three equal groups (n=8 in each), and the right eyes received 0.1-ml intravitreal injections of S. epidermidis suspension. The left eyes served as uninfected controls and were injected with 0.1 ml of saline solution. The right eyes of rabbits in group 1 were treated with intravitreal injection of 250 mu g/0.1 ml piperacillin/tazobactam 24 h after intravitreal inoculation of S. epidermidis whereas group 2 eyes received intravitreal 1 mg/0.1 ml vancomycin. Group 3 eyes received no treatment and served as infected controls. Clinical examination of the eyes in each group was performed on the 1st, 3rd and 6th day after the inoculation of S. epidermidis. On the 6th day, 0.1-ml vitreous aspirates were obtained for microbiological analysis, and then the eyes were enucleated for histopathological evaluation. Results: There were no statistically significant differences in mean clinical scores between the groups on the first day after S. epidermidis inoculation (p>0.05). On the 6th day, the mean clinical score of group 3 was significantly higher ( p<0.001), but the mean clinical scores of groups 1 and 2 were similar (p=0.812). The mean logarithmic value of colony-forming units per milliliter of groups 1, 2 and 3 were 0.6 +/- 1.3, 0.5 +/- 1.5 and 5.3 +/- 0.7, respectively. Mean histopathological scores of the groups were 8.3 +/- 0.9, 7.5 +/- 1.3 and 15.6 +/- 1.2, respectively. Group 3 eyes had significantly more colony-forming units per milliliter and a higher histopathological score (for each, p<0.001), and there were no statistically significant differences in microbiological and histopathological scores between groups 1 and 2 (for each, p>0.05). Conclusion: Intravitreal application of 250 mu g/0.1 ml piperacillin/tazobactam seems to be approximately equally effective with intravitreal 1 mg/0.1 vancomycin application in the treatment of experimental S. epidermidis endophthalmitis. Therefore, intravitreal piperacillin/tazobactam may be an alternative therapeutic option in the treatment of S. epidermidis endophthalmitis. Copyright (C) 2005 S. Karger AG, Basel.