An observational, prospective, longitudinal cohort study was performed at the AIDS Clinic of a tertiary care institution in Mexico City to determine the association of viral load (VL) and CD4+ lymphocyte kinetics with the development of oral candidosis (OC) and hairy leukoplakia (HL). Participants were HIV-infected adult subjects, without a history of or current OC or HL, not receiving HAART. Oral examinations were performed at baseline and every month for evidence of OC or HL; CD4+ and VL determinations were done at baseline, at 6-month intervals, when oral lesions were detected, and 2 months later. Affected subjects (OL group) by OC or HL had clinical intervals defined before (antecedent), during (concurrent), and after their development. In the nonaffected individuals (NA group), 6-month intervals were determined. Differences (changes) along the clinical and study intervals were calculated for CD4+ and VL. The median study time was 178 (range: 31-924) days; 99 patients were included. The 2-year cumulative incidence of either oral lesion was 54% (49.5% for OC and 33.2% for HL). In the OL group (31 patients) a progressive and continuous decrease of CD4+ was found in the antecedent interval followed by a significant increase in VL in the concurrent period. The NA group showed a significant fall in CD4+ by semester 3, without a significant rise of VL in the following semester. The effect of CD4+ remained significant in a multivariate analysis. This study has shown that the onset of OC and/or HL is heralded by the sequence of a sustained reduction of CD4+, followed by a sharp increase of VL. In the multivariate analysis, the decrease in CD4+ lymphocytes appeared to be the predominant factor predicting the appearance of these oral lesions. Their potential use as markers of a recent change in the immunologic and virologic status of HIV-infected individuals is emphasized.