Although human papillomavirus (HPV) antigens are expressed in a majority of (pre)neoplastic lesions (squamous intraepithelial lesions; SILs) of the uterine cervix, progression to invasive cancer may occur, which suggests that the presentation of viral antigens to the immune system is deficient in some SILs. To determine whether professional antigen-presenting cells die in SILs, we assayed for the apoptosis of immature dendritic cells (DC) in organotypic cultures of HPV-transformed keratinocytes, which reproduce many features of in vivo observed SILs. Unexpectedly, the infiltration of organotypic cultures by DC specifically induced the apoptosis of HPV+ tumor cells, whereas DC were not affected. In the same conditions and in coculture experiments, apoptosis was not observed in normal keratinocytes. The induction of apoptosis required membrane contacts between DC and HPV-transformed keratinocytes. Although the HPV+cell lines were sensitive to the effects of TRAIL, soluble TRAILR2-Fc did not block the DC-induced apoptosis. Furthermore, although FasL and Fas were detected on DC and HPV+ cell lines, respectively, functional analysis revealed that this pathway is not responsible for the apoptosis induced by the DC. All together these results suggest that DC may be at the interface between innate and adaptive immunity by inducing the apoptosis of (pre)neoplastic cells.