To assess the long-term and short-term effects of post-cataract surgery antibiotic therapy on the drug-resistance profile of normal conjunctival bacterial flora.Miyata Eye Hospital, Miyazaki, Japan.Randomized prospective clinical trial.Patients aged 20 years or older who had cataract surgery between May and September 2015 were given levofloxacin 1.5% ophthalmic solution for 3 days preoperatively. The patients were randomly assigned to a 1-week postoperative group or a 1-month postoperative group according to postoperative administration duration. Conjunctival sacs were scraped for bacterial culturing before administration, 1 week postoperatively, at the completion of administration, and 1, 3, and 6 months after administration completion. The bacterial culture growth and minimum inhibitory concentrations (MICs) of levofloxacin against recovered strains of Staphylococcus epidermidis were assessed.The study enrolled 104 patients. The MICs of levofloxacin against S epidermidis increased during levofloxacin administration compared with before administration in both groups and then declined after administration completion. However, by 3 months, the MICs in the 1-month group were approximately twice those in the 1-week group. Antibiotic susceptibility before administration, at completion of administration, and at 3 months was 73.6%, 20.2%, and 38.5%, respectively, in the 1-week group and 63.0%, 0.0%, and 19.3%, respectively, in the 1-month group. The results indicate that from completion of administration to 3 months, the susceptible strains were approximately 20% lower in the 1-month postoperative group than in the 1-week postoperative group.Administration duration of perioperative levofloxacin 1.5% influenced the MICs and susceptibility of S epidermidis isolated from the conjunctival sac.