Men with genital ulcer disease (GUD) attending a clinic in Malawi were evaluated and treated with one of five drug regimens. Haemophilus ducreyi was isolated from 204 (26.2%) of 778 patients. Of 677 men, 198 (29.2%) had treponemes detected in ulcer material by direct immunofluorescence or had rapid plasma reagin reactivity of > or = 1:8. Human immunodeficiency virus type 1 (HIV-1) seroprevalence was 58.9% overall and 75.8% among patients reporting a history of GUD (P < .001). By logistic regression analysis, HIV-1 seropositivity was shown to impair ulcer healing (P = .003). Treatment failure rates for culture-proven chancroid were 19% for trimethoprim-sulfamethoxazole, 12.9% and 7.4%, respectively, for low- and high-dose erythromycin regimens, and 8.3% and 0, respectively, for low- and high-dose ciprofloxacin regimens. Herpes antigen was detected by EIA in 6 (23.1%) of 26 nonhealing ulcers. In Malawi, GUD should be managed as a syndrome to assure treatment of both syphilis and chancroid.