We showed that, unlike pathogenic rabies virus (RV) strain CVS, attenuated RV strain ERA triggers the caspase-dependent apoptosis of human cells. Furthermore, we observed that the induction of apoptosis is correlated with a particular virus antigen distribution: the overexpression of the viral G protein on the cell surface, with continuous localization on the cytoplasmic membrane, and large cytoplasmic inclusions of the N protein. To determine whether one of these two major RV proteins (G and N proteins) triggers apoptosis, we constructed transgenic Jurkat T-cell lines that drive tetracycline-inducible gene expression to produce the G and N proteins of ERA and CVS individually. The induction of ERA G protein (G-ERA) expression but not of ERA N protein expression resulted in apoptosis, and G-ERA was more efficient at triggering apoptosis than was CVS G protein. To test whether other viral proteins participated in the induction of apoptosis, human cells were infected with recombinant RV in which the G protein gene from the attenuated strain had been replaced by its virulent strain counterpart (CVS). Only RV containing the G protein from the nonpathogenic RV strain was able to trigger the apoptosis of human cells. Thus, the ability of RV strains to induce apoptosis is largely determined by the viral G protein.