The role of human papillomavirus (HPV) in human disease includes external genital and perianal warts (EGW), with some HPV genotypes having oncogenic potential (i.e., HPV-16 and -18). While green-tea extracts have antitumor and antiproliferative effects in vitro, the mechanism of action of sinecatechins in the treatment of EGW is not well understood. To investigate the role of immune-regulated genes further, an open-label, single institution, prospective study was conducted enrolling patients with clinically diagnosed EGW. Thirty subjects were enrolled, and 18 completed the trial. All patients applied sinecatechins 15% ointment to target lesions in the study. RNA expression microarrays were obtained from treated EGW lesions and analyzed for differential gene expression of immune-regulated genes. HPV types were analyzed and, based on copy number, were stratified into virological responders (VR) or nonresponders (VNR). Gene expression analysis of RNA samples was performed using TaqMan arrays for human T cell receptor and CD3 complex (TCR), Toll-like receptors (TLR) pathway, interferon (IFN) pathway, and antigen processing pathway. A total of 256 genes were analyzed across the four arrays. Genes that were significantly regulated between VRs and VNRs were CREB3L4, HIST1H3A, HIST1H3H, IFNA1, IFNA4, IFNA5, IFNA6, IFNA8, IFNA14, IFNG, IFNAR1, IL6, IRF9, MAPK4, MAPK5, MAPK14, NET1, and PIK3C2A in the IFN array. In the TCR array, HLA_B was found to be statistically significantly upregulated in both the VR and VNR groups; concomitantly, CD8A was found to be statistically significantly downregulated only in VRs. In the TLR array, only LBP and MAPK8 were found to be differentially regulated. In the antigen processing array, HLA-A, HLA-C, HLA-DMA, HLA-DMB, HLA-F, PSMA5, PSMB8, and PSMB9 were differentially downregulated. Based on these findings, it was determined that sinecatechins treatment modulates and downregulates genes involved in the pro-inflammatory response to HPV infection.