Local hyperthermia has been successfully used in the treatment of viral warts. However, the mechanism of action of hyperthermia has largely remained unclear. In this study we evaluated the effect of local hyperthermia on the induction of apoptosis in human keratinocytes, and expression of apoptosis-related genes in both condyloma acuminata (CA) and normal skin. The study showed that higher hyperthermia increased the number of apoptotic keratinocytes in CA and normal skin. The temperature-dependent increased expression of Fas and Bax were observed in both CA and normal skin. In contrast, the expression of Bcl-2 in CA was decreased at both transcriptional and translational levels. Furthermore, the transcriptional expression of DR4 and DR5 were increased in a temperature-dependent manner in CA, but not in normal skin. These results suggest that different mechanisms of action might be involved in hyperthermia induced apoptosis in CA and normal skin.