Approximately 500 HIV-1 protease gene (pro) sequences were obtained from oral tissues (gingival cuff, buccal mucosa, tongue, palate) as well as saliva and peripheral blood mononuclear cells (PBMC) of 80 HIV-1 positive patients by nested amplification and manual sequencing of PCR products. By visual inspection each patient in this study exhibited a unique sequence profile. HIV-1 pro sequences obtained from patients with oropharyngeal candidiasis (OPC(+) patients) had significantly higher numbers of mutations than sequences from OPC(-) patients, but OPC(+) patients were no more likely to accumulate protease inhibitor resistance mutations than OPC(-) patients. Although the sequences for each patient were predominantly consistent between PBMC and oral tissues, approximately 10% of the patients demonstrated tissue specificity, and patients that demonstrated tissue specificity tended to be OPC(+). Furthermore, HIV-1 pro sequences derived from OPC lesions demonstrated unique mutations in approximately 30% of the patients who provided paired OPC(+/-) samples of the same tissue type. These data provide evidence for minimal compartmentalization of HIV-1 in oral tissues, yet some patients demonstrate minor variation between the HIV-1 pro sequences obtained from an OPC lesion and those obtained from a non-lesion site of similar tissue.