This article describes the baseline findings from a study designed to compare the oral manifestations of HIV infection in homosexual men and intravenous drug users. Both seropositive and seronegative persons were studied. A standard examination instrument was developed to record indexes of oral disease as well as to record the presence of oral lesions. The two groups differed in terms of education, race, socioeconomic status, employment status, housing, and smoking experience. The prevalence and type of oral lesions differed in the two seropositive groups. In seropositive homosexual men, white lesions on the tongue (28.4%) predominated; whereas for the seropositive intravenous drug users, oral candidiasis (43.0%) and gingival marginal erythema (33.3%) were most often detected. We also observed that seronegative intravenous drug users displayed a greater number of oral lesions than seronegative homosexual men. For seropositive homosexual men, lesion presence was significantly associated with decreased levels of CD4; positive associations were seen with current smoking, antiviral drug use, and antibiotic use, and a negative association was observed with current employment. In contrast, only exposure to antiviral drugs was significantly correlated with lesion presence for seropositive intravenous drug users. This baseline analysis from our longitudinal study suggests clear differences in oral manifestations of HIV infection between seropositive homosexual men and intravenous drug users and between seronegative homosexual men and intravenous drug users. Among other parameters, it is apparent that lifestyle, access to health care, and the condition of the oral cavity before infection influence the development of oral lesions in persons with HIV infection.