Background/Aims. Myofibroblast - like cells originating from the activation of hepatic stellate cells (HSC/MFs) play a key role in liver fibrosis, a potentially reversible process that may rely on induction of HSC/MFs apoptosis. While this possibility has been shown in cultured rat HSC, very limited data are currently available for human HSC/MFs. Methods. Cultured human HSC/MFs were exposed to several pro-apoptotic stimuli, including those known to induce apoptosis in rat HSC/MFs, and induction of cell death and related mechanisms were investigated using morphology, molecular biology and biochemical techniques. Results. In this study we report that fully activated human HSC/MFs did not undergo spontaneous apoptosis and survived to prolonged serum deprivation, Fas activation, or exposure to NGF, TNFa, oxidative stress mediators, doxorubicin and etoposide. Induction of caspase-dependent, mitochondria - driven apoptosis in HSC/MFs was observed only when protein synthesis or transcription were inhibited. Importantly, the process of HSC activation was accompanied by changes in the expression of a set of genes involved in apoptosis control. In particular, activated human HSC/MFs in culture overexpressed Bcl-2. The role of Bcl-2 was crucial since Bcl-2 silenced cells became susceptible to TNFa - induced apoptosis. Finally, Bcl-2 is markedly expressed in HSC/MFs present in liver tissue obtained from patients with HCV-related cirrhosis. Conclusions. Human activated HSC/MFs are resistant to most pro-apoptotic stimuli due to Bcl-2 overexpression and this feature may play a key role in the progression of fibrosis in chronic liver diseases.