Abstract Background and Aims: Hepatitis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has emerged as a major public health problem throughout the world. Dysregulation of apoptosis, autophagy and the unfolded protein response (UPR) has been implicated in a wide spectrum of human diseases including viral infection. These pathways are tightly interconnected and their crosstalk is a key factor for cell-fate determination in response to different stimuli. However, their interplay during HBV and HCV infection remains unclear. In this study we investigated induction of autophagy, UPR, and apoptosis in HBV- and HCV–infected human liver tissues to examine the importance of these pathways in HBV- and HCV-induced liver damage. In addition, these studies will pave the way for the development and application of therapeutics that modulate these pathways to affect HBV and HCV replication and the progress of liver damage in patients. Methods: We performed immunofluorescence (IF) confocal microscopy on 10 liver biopsies from HBV and HCV patients and tissue microarrays of HBV positive liver samples. We used specific antibodies for LC3β, cleaved caspase-3, BIP (GRP78), and XBP1 to detect autophagy, apoptosis and UPR, respectively. Anti-HCV NS3 and anti-HBs antibodies were also used to confirm infection. Results: Apoptosis, autophagy, and UPR were significantly higher (P<0.001) in the HCV- and HBV-infected, as compared to non-infected, cells of the same biopsy sections. XBP splicing was significantly higher in HBV-infected cells (P<0.05) while it was not significantly higher in HCV-infected cells (P>0.05). Conclusion: The results of this study indicate that HCV and HBV infection activates apoptosis, autophagy and UPR, but slightly differently by each virus. Further studies are warranted to elucidate the interconnections between these pathways in relation to pathology of HCV and HBV in the liver tissue.