Successful immune response to viral infection, such as human papillomavirus (HPV) infection, involves presentation of viral antigens to the immune system, recruitment of T cells and macrophages, and activation of a diverse array of cytokines. Interferons (IFN) are known to exert immunomodulatory functions via activating these pathways. However, the presence of HPV can interact with this process. We employed a reverse transcription-polymerase chain reaction (RT-PCR)-based method to study this phenomenon in biopsies of patients responding well or poorly to IFN treatment. We found that responders show a delayed-type hypersensitivity (DTH) reaction after IFN treatment, in which TH1 cells (interleukin-2, IL-2, IFN-gamma) and macrophages/NK cells (CD16) predominate. Antigen presentation capability (e.g., upregulation of MHC molecules, cytokines) is also enhanced after IFN treatment in responders. The lack of upregulation of MHC molecules (HLA-DR, beta 2-microglobulin) and certain cytokines (IL-1 alpha, IL-2, IFN-gamma) in nonresponders may be due to the overexpression of HPV early (E7) gene in contrast to responders, where HPV late (L1) gene expression predominates. We concluded that differential HPV expression in infected cells can be responsible for an inappropriate IFN-mediated immune response.