Trifluoperazine(TFP) is a well known antipsycotic phenothiazine derivative. TFP is also known as a calmodulin antagonist in molecular level. Although there have been many reports on the role of TFP on cell injury via calmodulin mechanism, the results are controversial on cell protection. Our purpose is to assess the effect of TFP on the PC12 cell injury in normal and hypoxic condition. The degree of cell injury was assayed by measuring LDH release and DNA fragmentation. DNA fragmentation of PC12 cells in normal culture condition for 24 hours after addition of TFP was increased in proportion to the TFP concentration. The TFP (10(-6)M) accelerated DNA fragmentation by 15% of total DNA in 24 hours incubation without significant changes of LDH release. TFP added in hypoxic cells for 2 hours increased the DNA fragmentation and LDH release by 60% and 30% respectively more than those not treated with TFP in the hypoxic condition. TPA(10(-8) M) reduced the DNA fragmentation and increased the LDH release induced by combination of TFP and hypoxia. The expression of p53 protein was not changed by hypoxia and TFP. Bcl-2 protein was increased by hypoxia by 40% and the increase was blocked by TFP. The TFP blocking effect on the increased Bcl-2 was releaved by TPA. These results suggested that the TFP accelerate PC12 cell apotosis in normal and hypoxic conditions in related to Bcl-2 expression.