The most common high-risk human papillomavirus types, HPV16 and 18, differ markedly with respect to their interaction with the host. Clearance of HPV18 infections generally takes longer and HPV18-positive cancers have a poorer prognosis. We therefore evaluated Th1-type immunity against the E6 and E7 oncoproteins of HPV18 in healthy subjects and in patients with HPV18-positive genital cancer, and compared the results to our previously obtained data for HPV16. Approximately 20% of the healthy individuals displayed immunity against HPV18 E6. In contrast, none of the patients showed such responses, despite the presence of HPV18-positive lesions. Several of the patients did respond to HPV18 E7, whereas this immunity is rarely found in healthy subjects. This pattern of immune reactivity is essentially similar to that previously found for HPV16. It is unlikely that this similarity is the result of immunological cross-reactivity between the E6 and E7 antigens of HPV types 16 and 18. Our data confirm the relation between failure of E6-specific Th1 immunity and high-risk HPVinduced cervical neoplasia and argue that parameters other than these determine the differences in pathological impact between HPV types 16 and 18. ' 2005 Wiley-Liss, Inc.Key words: HPV18; healthy individuals; cervical cancer patients T-cell immunity One of the most common sexually transmitted diseases is genital infection with the human papillomavirus (HPV). Although most of the infections are cleared within~1 year, persistent infection with high-risk types HPV can ultimately result in development of anogenital cancers. 1 The most common high-risk HPV type in infection is HPV16 (2-year cumulative incidence of 7%) followed by HPV18 with a 2-year cumulative incidence of 4%. 2 Although HPV16 and 18 are both high-risk HPV types, they differ at several aspects. In general, HPV16 infections are cleared within 12 months, whereas clearance of HPV18 may take 17 months. 2,3 In addition, HPV16-DNA can be found in neoplastic cells as episomal and/or integrated forms. Conversely, HPV18-DNA is only found integrated in the host DNA, even in preneoplastic regions. 4 Furthermore, HPV16 is often present in squamous cell carcinomas, whereas HPV18 is generally detected in adenocarcinomas. 5,6 Finally, HPV181 tumours behave more aggressively than HPV161 tumours, in that patients bearing HPV181 tumours have a poorer prognosis and a shorter diseasefree survival. 7,8 Despite the marked differences between the two types of viruses, immunity to HPV16 is studied in great detail and HPV18 is grossly neglected. So far, only the serological response to HPV18 has been documented. 9,10 Studies on the HPV18-specific T-cell immune response are scarce and limited to the identification of potential CTL epitopes 11,12 or vaccine-induced immunity. 13,14 Our studies on the presence and type of HPV16 E2-, E6-and E7-specific T-cell immunity in healthy subjects suggested that type 1 T-helper cell reactivity against HPV16 E2 and E6, which was present in the great majority of healthy individual...