Human immunodeficiency virus (HIV) infection is associated with dysplastic changes in oral human papilloma virus (HPV) lesions, suggesting changes in keratinocytes. In the present study, we seek to identify proteomic changes in oral HPV lesions between HIV(+) and HIV(-) patients. While fresh tissues represent the most desirable samples for proteomic investigations, they are often difficult to obtain in large numbers under clinical settings. We therefore have developed a new method to identify protein changes in formalin fixed and paraffin-embedded (FFPE) oral HPV lesions utilizing iTRAQ™ technology in conjunction with Liquid Tissue® sample preparation method. Using this method, we identified nine proteins that were differentially expressed in oral HPV lesions as a result of HIV infection. The quantitative proteomic method presented here will be valuable for others who plan to analyze FFPE tissues.