The alpha-herpesvirus Varicella-Zoster Virus (VZV), the causative agent of chicken pox, infects most humans worldwide and remains latent in peripheral neuronal cells for life. Its reactivation triggers herpes zoster and sporadic disseminated infection, in particular in the central nervous system (CNS) where it is associated with severe pathologies. VZV replication is efficiently controlled with antivirals, however the emergence of treatment-resistant VZV variants constitutes an increasing healthcare issue, calling for in-depth analysis of molecular VZV-host interactions to foster general knowledge and promote identification of novel therapeutic targets. Here we conducted a mass spectrometry-based survey in neuronal SK-N-BE2 cells, combining proteome analysis of VZV-infected cells with systematic characterization of VZV proteins’ functions through identifying their individual host partners and effects on the host proteome. In this dataset, we systematically assessed proteome changes elicited by the expression of individual viral proteins – the so called “effectome”, which allowed us to gain unprecedented insights in the activity of individual VZV ORFs.