The levels of type-I and type-II soluble TNF-␣ receptors (sTNF-Rs) were evaluated in sera from patients with various human-papillomavirus-(HPV)-associated benign and malignant anogenital lesions using specific enzyme-linked immunobiological assays. In patients with benign HPV6/11-associated condylomata acuminata, the levels of sTNF-RI were significantly increased, while sTNF-RII were in normal range. Both types of sTNF-Rs were in normal range in patients with benign HPV16-associated grade-I/II and grade-III cervical intra-epithelial neoplasia. However, their levels were significantly increased in patients with HPV16/18-associated squamous cervical cancer and anogenital Bowen's carcinoma. Sera from patients with condylomata acuminata and anogenital carcinomas displayed significantly increased TNF-␣inhibitory activity, as revealed by L929 cell-cytotoxicity assay. Increased serum TNF-␣-inhibitory activity correlated with higher levels of sTNF-Rs. Furthermore, this inhibitory activity could be specifically abrogated by htr9 and utr1 monoclonal antibodies recognizing TNF-RI and TNF-RII respectively. Our results strongly suggest that serum sTNF-Rs may protect tumor cells from cytotoxic/cytostatic effects of locally released TNF-␣, and that elevated levels of circulating sTNF-Rs may facilitate the growth of HPV-associated anogenital lesions. Int.