Human papillomaviruses (HPVs) are small DNA viruses, which specifically infect keratinocytes at different body sites. The association between cutaneous squamous cell carcinoma (SCC) formation, ultraviolet (UV) irradiation and infection with a high-risk subset of cutaneous HPVs has been postulated although the underlying molecular mechanisms by which HPV may play a role in SCC development are not yet fully elucidated. Expression of the viral E6 oncoprotein has been shown to interfere with DNA damage responses and inhibit UV-induced apoptosis, suggesting HPV can contribute to early stages in tumorigenesis. However, cutaneous SCCs, in contrast to HPV-associated anogenital cancers do not harbor HPV DNA in every tumor cell. Here, we show that expression of E6 from the prototypic skin cancer-associated HPV type 5 induced the secretion of factors that were able to inhibit UV-induced apoptosis in non-HPV-expressing cell lines and primary human keratinocytes. The anti-apoptotic effect of HPV E6 expression was found to be mediated in part by upregulation of osteoprotegerin (OPG) and interleukin 6 (IL6). Purified OPG and IL6, when added to cells together, but not individually, reduced apoptosis following UV irradiation. We provide evidence that OPG and IL6 inhibit the extrinsic and intrinsic apoptotic pathways, respectively. Furthermore, we show by immunohistochemistry of HPV-typed SCC sections that IL6 protein is upregulated in HPV-positive tumors compared with HPV-negative cancers. These findings support the hypothesis that a small number of HPV-infected cells influence UV-induced apoptosis in the skin and contribute to tumorigenesis.