Nonconcurrent analysis of 45,954 cataract operations performed by a single surgeon indicates that periocular injection of penicillin combined with multiple preoperative applications of topical chloramphenicol-sulphadimidine reduced the incidence of postoperative endophthalmitis by 72%. Periocular penicillin alone was ineffective. A concurrent masked randomized study of 6,618 cataract operations confirms the efficacy of combined prophylaxis and demonstrates that the topical regimen, by itself, is as ineffective as isolated penicillin prophylaxis.