Medical records of 341 patients with syphilis seen at a health department sexually transmitted disease clinic were reviewed to assess membership in high-risk subgroups and interactions with human immunodeficiency virus (HIV) infection. When compared with the entire clinic population, patients with syphilis tended to be older and were more likely to acknowledge intravenous drug use, more often had a history of syphilis, and, among men, were more often homosexually active. Half of the men with syphilis and one third of the women fell into one or more of these high-risk subgroups. Patients with syphilis were also more likely to test positive for HIV infection than other patients attending the clinic. Patients admitting to intravenous drug use, prior syphilis, or being homosexually active were significantly more likely to be HIV seropositive than patients without these characteristics, even though patients with these characteristics were significantly more likely to refuse HIV serologic testing. Although clinical stage of syphilis at presentation did not differ when patients with and without concurrent HIV infection were compared, geometric mean rapid plasma reagin titers were significantly higher in HIVinfected patients with secondary syphilis. © 1991, American Medical Association. All rights reserved.