Objectives: To compare clinical presentations of patients with early syphilis who did or did not have human immunodeficiency virus (HIV) infection. Design: Case-control study. Setting: The sexually transmitted diseases clinics of the Baltimore City Health Department. Patients: Patients with newly diagnosed primary, secondary, or early latent syphilis who had voluntary HIV testing from January 1990 to November 1991. Measurements: Data on sexual history, risk behaviors, and physical findings (before knowledge of HIV or syphilis serologic test results) were extracted from clinical records. Diagnoses of syphilis were confirmed by reactive syphilis serologic tests. Rapid plasma reagin titers reported to the disease registry of the Baltimore City Health Department were abstracted to determine therapeutic response. Patients positive for HIV who returned for follow-up had further counseling, staging, and CD4 lymphocyte testing. Results: Data were available on 309 of 527 patients with early syphilis: 108 patients with primary syphilis, 116 with secondary syphilis, and 85 with early latent syphilis. Seventy (23%) patients had concurrent HIV infection. Patients with HIV infection presented more often with secondary syphilis than did patients with syphilis who were HIV seronegative (53% [37 of 70] compared with 33% [79 of 239]; P = 0.01). The same was true for heterosexual men with HIV infection (46% [16 of 35]) compared with heterosexual men without infection (25% [35 of 142]; P < 0.03). Among those who denied intravenous drug use, 59% (22 of 37) of patients with HIV infection presented with secondary syphilis compared with 33% (65 of 198) of patients without infection (P < 0.01). Among patients with first episodes of syphilis, patients positive for HIV who had secondary syphilis were more likely to present with persistent chancres (43% [9 of 21] compared with 15% [11 of 72]; P = 0.01). The rate of decline in the rapid plasma reagin titers during a 12-month period after treatment did not differ between patients with and without HIV infection (P = 0.15). Conclusions: The clinical presentation of syphilis in patients with HIV infection differs from that of patients without HIV infection in that patients with HIV infection present more often in the secondary stage and those with secondary syphilis are more likely to have chancres.