We conducted a randomized clinical trial comparing a single intramuscular dose of 125 mg of ceftriaxone with a single intramuscular dose of 75 mg of kanamycin followed by topical gentamicin for seven days, and with a single intramuscular dose of 75 mg of kanamycin followed by topical tetracycline for seven days, in the treatment of gonococcal ophthalmia neonatorum in Nairobi, Kenya. Of 122 newborns with culture-proved gonococcal ophthalmia neonatorum, 105 returned for follow-up. Sixty-one infants (54 percent) received ceftriaxone, 32 received kanamycin plus topical gentamicin, and 29 received kanamycin plus topical tetracycline. Sixty-six (54 percent) of the Neisseria gonorrhoeae isolates were penicillinase producing. All 55 newborns who received ceftriaxone and returned for follow-up were clinically and microbiologically cured. One of 26 returning newborns who received kanamycin plus tetracycline and 2 of 24 returning newborns who received kanamycin plus gentamicin had persistent or recurrent gonococcal conjunctivitis. Ceftriaxone also eradicated oropharyngeal gonococcal infection in 18 newborns, whereas oropharyngeal infection persisted in 2 of 8 newborns who had received kanamycin (P not significant). We conclude that 125 mg of ceftriaxone as a single intramuscular dose is very effective therapy for gonococcal ophthalmia neonatorum, with marked efficacy against extraocular infection and without the need for concomitant topical antimicrobial therapy.