Chancroid is linked to the spread of human immunodeficiency virus type 1 (HIV-1) in East Africa. Effective, easily administered therapy is a priority for the control of Haemophilus ducreyi. The efficacy of a single oral dose of fleroxacin, 400 mg, was compared to a 3-day oral course of trimethoprim-sulfamethoxazole (TMP-SMZ), 160/800 mg, twice daily for the treatment of chancroid in 98 HIV-1-seronegative men in Nairobi, Kenya. No differences were noted between the two groups with respect to demographic characteristics, sexual behavior, and clinical characteristics. Culture-proven failure occurred in 1 (3%) of 36 fleroxacin-treated patients and in 11 (30%) of 37 TMP-SMZ-treated patients (P = .005). Fleroxacin, as a single oral dose, is an effective treatment for culture-proven chancroid in patients who are HIV-1 seronegative. TMP-SMZ is no longer predictably effective due to the recent emergence of resistance to both sulfonamides and to trimethoprim.