We have previously reported that primary sinusoidal endothelial cells from the rat liver are highly dependent on VEGF for cell proliferation in in vitro culture. However, even in the presence of VEGF, essentially all the SE cells could not survive longer than 7 days, leading to growth factor-resistant cell death. The death had characteristics typical of apopotosis, such as DNA fragmentation, staining with TUNEL reagent and nuclear condensation. We found that the cell death was blocked by the treatment of TPA in a dose-dependent manner and was preceded by a remarkable increase in PKC delta at a protein level. Furthermore, PKC delta -specific inhibitor, Rottrelin, significantly suppressed this VEGF-resistant apoptosis of cultured SE cells, whereas conventional PKC-specific inhibitor, Go6976 could not. TPA was found to downregulate the overexpression of PKC delta. Thus, we suggest that the VEGF-resistant apoptosis is a new type of endothelial cell death and that PKC delta is an essential mediator for this process.