To develop transplantation of neural stem/progenitor cells (NSPCs) as a successful treatment of neurodegenerative disorders, the possible induction of an inflammatory response following implantation needs to be taken into consideration. Inflammatory cytokines can upregulate major histocompatibility complex (MHC) expression on transplanted cells, thereby rendering them more susceptible to graft rejection. Furthermore, cytokines also have a profound effect on cell differentiation, migration, and proliferation, which can greatly affect the outcome of transplantation. Here we studied the effect of three inflammatory cytokines, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6), from three different species (human, monkey, rat) on expression of MHC molecules and differentiation of two human NSPC lines derived from striatum and hippocampus. Human and monkey IFN-gamma strongly upregulate MHC expression in both NSPC lines in a dose-dependent manner, whereas rat IFN-gamma has an effect on MHC expression only in hippocampal cells. Furthermore, TNF-alpha, but not IL-6, upregulates MHC expression in both NSPC lines. Differentiation of NSPCs in the presence of cytokines showed that IFN-gamma increased the neuronal yield threefold in striatal NSPC cultures and increased the number of oligodendrocytes twofold in hippocampal NSPC cultures. Addition of TNF-alpha enhanced gliogenesis in both cell lines, whereas IL-6 stimulated neurogenesis. Human NSPC lines' response to cytokines is therefore species specific and also dependent on the NSPCs' region of origin. The successful translation of different cell lines from animal models to clinical trials could be substantially influenced by the species-specific regulation of MHC and differentiation as reported here. Disclosure of potential conflicts of interest is found at the end of this article.