Apoptosis has recently been associated with herpes simplex virus 1 (HSV-1) latency and disease severity. There is an intricate balance between pro- and anti-apoptotic processes during HSV-1 infection. When anti-apoptotic pathways are suppressed, this balance is upset and the cells die by apoptosis, referred to here as HSV-1-dependent apoptosis (HDAP). It has been observed previously that HeLa cancer cells exhibit an enhanced sensitivity to HDAP. Here, a series of specific patient-derived cancer cells was utilized to investigate the cell-type specificity of HDAP. The results showed that a human mammary tumour cell line was sensitive to HDAP, whilst syngeneic normal cells were resistant. Furthermore, low-passage-number primary human mammary epithelial cells were resistant to HDAP. When the susceptibility of human colon, brain, breast and cervical cancer cells was assessed, the only cells insensitive to HDAP were those resistant to all environmental stimuli tested. This implies that the HDAP resistance was probably due to mutations in the cellular apoptotic machinery. Thus, the susceptibility of cancer cells to HDAP requires that they possess a functional ability to undergo programmed cell death.