We treated 289 men who had nongonococcal urethritis with minocycline, 100 mg once or twice daily for 7 to 21 days. After 21 +/- 7 days, urethritis persisted or recurred in 31 (27%) of 114 given 7-day therapy and only nine (8%) of 110 given 21-day therapy (p = 0.0005). However, by 49 +/- 14 days, the cumulative percent rate of failure was 31% for 7-day and 30% for 21-day therapy. Thus, 21-day therapy only delayed recurrence. The higher daily dosage did not improve outcome. Urethritis persisted or recurred in 19% of men with initial Chlamydia trachomatis infection. Among men without C. trachomatis, urethritis persisted or recurred in 32% with and 52% without Ureaplasma urealyticum infection (p = 0.03). At follow-up, 79% of cases of persistent or recurrent urethritis were culture negative for C. trachomatis and U. urealyticum. The cause of C. trachomatis-negative, U. urealyticum-negative nongonococcal urethritis, which was least responsive to minocycline therapy, remains uncertain.