Varicella zoster virus (VZV) is an exclusively human alphaherpesvirus, which causes varicella (chickenpox) upon primary infection while establishing lifelong latency in neurons of the dorsal root ganglia. Subsequent reactivation of VZV presents as herpes zoster (shingles), which can cause significant morbidity in the ageing population. The mechanisms by which VZV establishes latency and reactivates are not well understood, however it has been suggested that viral inhibition of neuronal apoptosis plays an important role. We have previously shown that VZV immediate-early tegument protein ORF63 is essential in protecting rat neurons from apoptosis. It is unknown however, whether this phenotype is recapitulated in human cells, and the mechanism of action is yet to be discerned. To understand the anti-apoptotic effects of VZV-ORF63 in human cell types critical for VZV pathogenesis, novel neuroblastoma (SH-SY5Ys) and skin keratinocyte (HaCaT) cell lines expressing VZV-ORF63, were created through lentiviral transduction. We then induced intrinsic apoptosis by staurosporine, or extrinsic apoptosis by Fas ligand (FasL) in these VZV-ORF63 expressing cell lines. Via immunofluorescence for cleaved caspase-3 (CC3) and DNA fragmentation (TUNEL), we found that VZV-ORF63 expressing SH-SY5Ys were significantly less CC3 and TUNEL positive after staurosporine treatment. This demonstrates for the first time that VZV-ORF63 can protect human neuronal cells from apoptosis. Similarly, VZV-ORF63 expressing HaCaTs were significantly less CC3 positive in response to both staurosporine and FasL. Together the data illustrate that the protective effect of VZV-ORF63 is not specific to neurons or type of apoptotic stimuli. To dissect the mechanism of action, the localisation of ORF63 protein was analysed by confocal microscopy in VZV-ORF63 expressing HaCaTs. Following staurosporine treatment, we observed VZV-ORF63 protein localisation became more cytoplasmic and formed aggregates, suggesting potential interaction with host cell proteins to prevent apoptosis. These findings begin to elucidate how VZV-ORF63 inhibits apoptosis, advancing our understanding of VZV pathogenesis.