The major envelope protein (E) of flaviviruses has multiple functions including in receptor binding, viral assembly, and induced protective immunity as well as apoptosis. The YL strain of JEV was investigated for its pathogenesis and apoptotic activities in Vero, HepG2 and neural C6 cells. In this study, YL strain caused different phenotypic properties in cell cultures which showed smaller plaque formation in HepG2 cells than in Vero cells, but no cytopathic effect in C6 cells. Furthermore, the viral E proteins were investigated for its apoptotic activities in Vero cells, HepG2 cells and neural C6 cells. First, we constructed four eukaryotic expressed plasmids of E protein, respectively named pcE, pcF1R2, pcF1R1 and pcF2R2. Then these plasmids were transfected to above cell lines and observed the expression of E protein by immuno-staining and detected apoptotic cell death with flow cytometry. In addition, these cleavage of cellular DNA of hallmark apoptotic cells were also confirmed by electrophoresis analysis. Our results showed the recombinant pcE, which comprises full-length E gene but not those deleted forms (pcF1R2, pcF1R1 and pcF2R2) could induce various degrees of apoptosis in Vero and HepG2 cell lines. The conclusion revealed that YL strain had cell tropism change and only the recombinant of full-length E protein (pcE) but not its deleted forms could induce apoptotic cell death.?