Little is known of the in vivo role of the immune system in controlling human papillomavirus infection in the genital tract. The authors have studied 125 closely monitored patients with genital warts. Of these 125 patients, wart regression was seen in 28 patients. This study provides evidence that clearance of human papillomavirus from the genital tract is characterized by an active cell-mediated immune response. Regressing warts (n = 14) contained significantly more T lymphocytes (P < .05, Wilcoxon rank sum test) and macrophages (P < .01) than did nonregressing controls (n = 14). CD4-positive lymphocytes predominated in regression, both within the wart stroma and the surface epithelium, where there was a significant change in the ratio of CD4+ to CD8+ cells (P < .01). Lymphocytes in regression also showed greater expression of activation markers, and the majority were of the "antigen-experienced" phenotype. There was no difference in Langerhans cell numbers, although there was significant induction of the immune accessory molecules HLA-DR and ICAM1 (P < .05) on keratinocytes, and E-selectin and VCAM1 (P < .05) on endothelial cells in regressing warts. The changes in regression are consistent with a delayed-type hypersensitivity reaction to foreign antigen, and the ability to induce and mount such a response may be a critical determinant of effective natural immunity to the genital HPVs. Specific targeting of delayed-type hypersensitivity responsiveness may increase the efficacy of strategies for immuno-intervention against HPV infection in the genital tract.