In the present study, biochemical and molecular changes during cell death induced by selenite and Se-methylselenocysteine (MSC) were studied in human promyelocytic leukemia (HL-60) cells. Treatment of selenite and MSC decreased cell viability in a dose-dependent manner measured by WST-1. Lactate dehydrogenase leakage assay indicated that selenite caused more extensive membrane damage than MSC. Morphological observations revealed that selenite-treated cells showed mainly necrotic morphologies and MSC-treated cells exhibited apoptotic morphologies. Although both selenite and MSC induced apoptotic DNA fragmentation in a dose-dependent manner, flow cytometric analysis of apoptosis revealed that apoptotic population was much higher in MSC-treated cells. Caspase-3, -8, and -9 were activated by both selenite and MSC, but the magnitude of their activation was much smaller in selenite-treated cells than in MSC-treated cells. On the other hand, the extent of cytochrome c release was much higher in selenite-treated cells, which implies that selenite caused extensive mitochondrial damage. Caspase inhibitors, z-DEVD-fmk, z-LEHD-fmk, and z-IETD-fmk all significantly recovered the decreased viability by the treatment with MSC, while they had no effects in case of selenite-treated cells. Caspase-3 activity was completely inhibited by z-IETD-fmk, whereas inhibition by z-LEHD-fmk was partial. These results suggest that caspase activation cascade mediated by caspase-8 is required for MSC-induced cell death while selenite-induced cell death occurred irrespective of caspase activation. Intracellular calcium level was increased by selenite and MSC. Calcium channel blocker $Ni^{2+}$ could significantly lower the intracellular calcium level and increase the viability in selenite-treated cells, which indicates that calcium influx is important in selenite-induced cell death. Further investigations on DNA strand breaks suggested that selenite caused caspase-3-independent DNA double and s...