Abstract: The cellular translation machinery is hijacked by large amounts of viral proteins upon virus infection. The unfolded proteins accumulated in the endoplasmic reticulum (ER) results in ER stress. ER stress is implicated in some plant virus infections that replicated in the ER. To investigate if Cucumber mosaic virus (CMV) that replicated in the tonoplast induces ER stress, ER stress gene expression by qRT-PCR, ER morphology by transient expression of mCherry-HDEL and confocal microscopy, and ultrastructure of cytopathology by electron microscope in CMV-IB inoculated Nicotiana leaves were compared with PBS buffer inoculated control. The results showed that the ER stress related genes were upregulated significantly at 12 hours post inoculation, with 1.23-7.37 folds higher levels in CMV inoculated leaves than in PBS controls (p<0.05). ER morphology was hyperplasia and significant rearrangement at 5-10 days post CMV inoculation. Ultrastructure of CMV-diseased cells showed chloroplast degradation, mitochondria swelling, invagination of tonoplast into two double membranous complex structures of microautophagy, and macroautophagic structures in the cytoplasm. This indicated that CMV infection induces ER stress including activating ER stress genes and causing ER proliferation. Host may activate organelles degradation, autophagy even cell death to suppress viral infection.