Background: Conflicting data exist regarding whether HIV infection leads to changes in the clinical manifestations and severity of genital ulcer disease (GUD). Goal: To determine the impact of HIV on the etiology and clinical severity of GUD. Study Design: From July 1990 to July 1992, consecutive patients presenting to the two Baltimore City Health Department (BCHD) Sexually Transmitted Diseases clinics were approached as candidates for enrollment in a prospective study to determine factors associated with the transmission and acquisition of sexually transmitted diseases (STDs). Results: Of the 1368 patients who presented to the BCHD, 214 (16%) had genital ulcerations: 160 (21%) of 757 men and 54 (9%) of 611 women. Among the patients with GUD who had undergone HIV testing, 28 (14%) of 204 were infected with HIV: 25 (17%) of 151 men and 3 (6%) of 53 women. Although both groups-those infected with HIV and those not infected with HIV-presented with GUD of similar duration (10 versus 11 days; P = 0.17), multiple lesions were found more frequently in men with HIV infection than in uninfected men: 87% versus 62% (P = 0.02). Although not statistically significant, GUD in men with HIV infection more often were deep (64% versus 44%, respectively) rather than superficial (36% versus 57%, respectively; P = 0.08), and larger (505 mm2 versus 109 mm2; P = 0.06). Primary syphilis caused more GUD among men with HIV infection than among uninfected men: 9 (36%) of 25 versus 24 (19%) of 126, respectively (P < 0.01). Secondary syphilis was diagnosed with concomitant GUD more frequently among men with HIV infection than among uninfected men: 3 (13%) of 25 versus 3 (2%) of 123, respectively (P < 0.01). Conclusions: In this study, patients who presented with GUD were more likely to be infected with HIV. A higher proportion of men with HIV infection had multiple lesions, and the lesions were more likely to be caused by syphilis.