To report two cases of acute and chronic-onset, postoperative Staphylococcus epidermidis endophthalmitis and discuss the virulence and treatment of this saprophytic pathogen. After clinical diagnosis of endophthalmitis, prompt vitreous culture was performed with injection of intravitreal vancomycin 1 mg/0.1 mL and ceftazidime 2.25 mg/0.1 mL. With no improvement after this procedure, a pars plana vitrectomy and lensectomy were performed to further decrease microbial load and repeat the intravitreal antibiotic. The lens and large amounts of fibrotic tissue were removed, and the posterior capsule was stripped. Vitreous cultures grew S. epidermidis sensitive to vancomycin. Intraoperative findings included dense vitreous opacification with extensive vitreous bands and pus extending into the zonules. During the removal of the IOL, adherent pus filaments were removed; however, only a moderate amount of bacteria was detected on the IOL. Further intravitreal vancomycin (1 mg/0.1 mL) and ceftazidime (2.25 mg/0.1 mL) were injected. Staphylococcus epidermidis is widely reported as responsible for medical device-related sepsis. This is mainly due to the production of slime, an exopolysaccharide that eventually leads to the formation of biofilm, one of the most important virulence factors. The failure of intravitreal antibiotic treatment in our two biofilm-associated infections may be due to the considerable amount of slime and pus found extending into the zonules and adherent to the IOL during surgery.