A retrospective review of the medical records of 492 children perinatally exposed to the human immunodeficiency virus (HIV) compared the prevalence of orofacial soft-tissue manifestations in HIV-infected and noninfected children, identified risk factors for occurrence of orofacial lesions in HIV-infected children, and investigated specific orofacial lesions as indicators of progression of HIV disease. Application of eligibility criteria and the Centers for Disease Control classification of pediatric HIV infection resulted in selection of a study group of 91 HIV-positive children and a control group of 185 HIV-seronegative children who had seroreverted. Analysis of oral lesions showed that 67% of the study group and 8% of the control group had oropharyngeal candidiasis (OPC), 4% of the study group and 0% of the control group had parotid enlargement, and 3% of the study group and 0% of the control group had herpes simplex; all three differences were significant at P < 0.04. No statistically significant association was found between OPC and the risk factors of gender, ethnicity, or mode of delivery (vaginal versus cesarean). However, OPC was associated significantly with all progression markers examined: failure to thrive, use of antiretroviral agents, lower CD4 counts, and development of acquired immunodeficiency syndrome (AIDS). Orofacial manifestations are common in pediatric HIV infection and may serve as markers of infection and predictors of progression of HIV disease to AIDS.