The recommendation by the Centers for Disease Control (CDC) that erythromycin and tetracycline ointments, as well as silver nitrate solution, are acceptable regimens for prophylaxis of gonococcal ophthalmia neonatorum (GON) has resulted in widespread local review of policies for ocular prophylaxis. The data concerning the efficacy and side effects of these agents are somewhat confusing or nonexistent. We discuss the etiologies of neonatal conjunctivitis and the topical and systemic agents used for prophylaxis of GON. We also review all studies that have compared the efficacy of one prophylactic agent with that of another agent or with no prophylaxis. It is found that all three agents have similar efficacy in preventing GON, although silver nitrate has been used more extensively in populations at high risk for GON. However, since Chlamydia trachomatis is the most common infectious cause of neonatal conjunctivitis in the United States at this time, and erythromycin appears to be very effective in prevention of neonatal conjunctivitis due to C. trachomatis, it may have an advantage over the other two agents. In addition, erythromycin use is associated with fewer ocular reactions than is silver nitrate.