This study was done to determine whether the increase in high-level tetracycline resistant Neisseria gonorrhoeae (TRNG) was associated with increased tetracycline use. From 547 persons with positive cultures seen consecutively at a sexually transmitted disease (STD) clinic, 51 (9%) isolates were resistant to tetracycline. Of these 51 isolates, 37 (73%) had high-level resistance (TRNG) which was mediated by the tetM determinant located on a 25.2-megadalton plasmid. Women were twice as likely as men to have TRNG. Previous visits to an STD clinic and oral antibiotic use for a sexually transmitted disease within a one to five month period were used as surrogates for prior tetracycline use. Patients who had been to an STD clinic were almost twice as likely to have TRNG (RR = 1.9, 95% CI: 1.01, 3.46), and those who took an oral antibiotic had a relative risk of 1.8. The authors postulate that previous tetracycline use selects for tetM-containing microorganisms in the genitourinary tract that, at the time of gonococcal infection, have the ability to transfer the determinant to N. gonorrhoeae. The above findings might have implications for modifying the current Centers for Disease Control (CDC) recommendation to prescribe tetracycline for suspected Chlamydia infection among patients with gonorrhea.