We treated 289 men with nongonococcal urethritis in a randomized, double-blind study with minocycline, 100 mg once or twice daily for 7 or 21 days. Ureaplasma urealyticum was isolated before treatment from 167 (58%). The pretherapy isolates from 82 men re-examined 6 to 8 days after initiation of treatment were viable. In six (7%) isolates were resistant to 256 microgram/mL or more of tetracycline. Tetracycline resistance was significantly correlated with persistence of U. urealyticum and persistence of nongonococcal urethritis during treatment. Recurrence of nongonococcal urethritis after initial resolution and recurrence of U. urealyticum after interim negative cultures were not correlated with tetracycline resistance of U. urealyticum. Thus tetracycline-resistant strains of U. urealyticum are a cause of persistent but not of recurrent nongonococcal urethritis.