Introduction: Background: Endophthalmitis is still one of the most fearsome complications of cataract surgery. The most important pathogens causing post-operative phacoemulsification endophthalmitis are staphylococci. Methods: 85 patients were included in a phase II pilot study. Patients were divided in three groups, group 1 and 3 received either azithromycin 1.5% eye drops or placebo eye drops one day before surgery and for 2 days after surgery and group 2 received azithromycin 1.5% eye drops for 3 days after surgery. Treatments were administered twice a day: one drop in the morning and one in the evening. Bacterial samples were collected three times from the conjunctival cul-de-sac, at D-2 (inclusion visit), D0 (before surgery) and D5 (final visit). In this pilot study, the primary endpoint was the proportion of positive cultures on the day of surgery (D0). Ocular and systemic safety data (including tolerance) were also recorded. Results: Among patients with a positive culture in the conjunctival cul-de-sac on D-2, 57.6% were still positive at D0 in group 1, versus 92.3% in group 3 (placebo group) (p=0.035). The number of staphylococcus colonies (log-transformed) decreased between D-2 and D0 and the difference is statistically significant between the three groups (p=0.043) and between group 1 (that received azithromycin 1.5% eye drops at D0) and groups 2+3 (that did not received azithromycin 1.5% eye drops at D0) (p=0.025). This difference was emphasized between group 1 and group 3 (placebo group) (p=0.015). No safety issue was raised during the study and 100% of patients were very satisfactory or satisfactory with the global tolerance of the eye drops. Conclusions: Azithromycin 1.5% eye drops are safe, and effective in reducing the bacterial load of conjunctival cul-de-sac, including the number of staphylococcus colonies, during the peri-operative period of cataract surgery. Clinical Trial: www.ISRCTN.org ISRCTN41154297