The authors conducted an open-label nonrandomized parallel trial to examine whether the preoperative application of povidone-iodine to the ocular surface reduces the incidence of endophthalmitis after intraocular surgery. During an 11-month period, topical 5% povidone-iodine was used to prepare the conjunctiva in 1 set of 5 operating rooms, while silver protein solution was used in another set of 5 rooms. In all cases, surgeons continued to use their customary prophylactic antibiotics. A significantly lower incidence of culture-positive endophthalmitis (P less than 0.03) was observed in the operating rooms using povidone-iodine (2 of 3489 or 0.06%) compared with those using silver protein solution (11 of 4594 or 0.24%). Use of topical povidone-iodine in over 3000 cases was not associated with any adverse reactions. In a majority of the observed cases of endophthalmitis, some form of intraoperative communication with the vitreous cavity existed.