Proliferation and matrix synthesis by activated pancreatic stellate cells (PSC) participate in the development of chronic pancreatitis. Apoptosis of PSCs may terminate this process, but has not yet been studied in this particular cell type and was the aim of the present study. PSCs were isolated from rat pancreas and characterized for expression of GFAP, -SMA, CD95 and TRAIL receptors. Apoptosis was determined by TUNEL-reaction, annexin V-binding, and caspase-8 activation. Both, CD95L and TRAIL induced apoptosis in PSCs. The apoptotic response was minor in PSC cultured for 7 days, but increased thereafter markedly. Sensitization of PSC with culture duration was accompanied by increased expression of CD95 and TRAIL receptor 2, no alterations of Flip expression or protein kinase B phosphorylation, but paralleled by the appearance of a c-terminal cleavage product of RIP. PSC apoptosis was also induced by PK11195, a ligand of the peripheral benzodiazepine receptor. PSC apoptosis may be important in terminating the wound-healing response following pancreas injury and exhibits features distinct from apoptosis induction in hepatic stellate cells.