To determine whether the addition of a bioadhesive drug-delivery system to topical azithromycin induces intraocular inflammation and damage when introduced intraocularly by different approaches and in varying doses. John A. Moran Eye Center, Salt Lake City, Utah, USA. Experimental study. Commercial topical azithromycin 1.0% was duplicated, including the benzalkonium chloride, but without inclusion of the Durasite bioadhesive drug-delivery system. Injections of 50 μL, 25 μL, and 10 μL of the antibiotic solutions were administered in a masked fashion to 2 rabbits; 1 eye (study eye) in each rabbit was randomized to receive azithromycin with the delivery system and the fellow eye (control eye) to receive azithromycin without the delivery system. Two rabbits had topical drops of each solution placed after a 2.8 mm incision was created. Masked slitlamp examinations, pachymetry, and intraocular pressure (IOP) were determined 1 day and 2 days postoperatively. The animals were humanely killed, and the endothelial density and histopathology were examined. The IOP (P<.001), pachymetry (P<.001), and signs of inflammation (P=.38 to .003) were consistently higher in the study eye, especially at the 50 μL dose, than in the control eye. This was confirmed by histopathology. If the drug-delivery system gains access to the anterior chamber, it may cause substantial corneal edema and inflammation, even at low doses and after topical administration.