Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays an important role in regulating hepatoma cell apoptosis. However, conclusions of different studies about the effects of HIF-1 alpha expression on hepatoma cell apoptosis remain controversial. Omi/HtrA2 promotes cell apoptosis in some human cancer cells. Our previous experiments have demonstrated that primary hepatocellular carcinoma may need Omi/HtrA2 expression for cell apoptosis. Thus, we investigated the effect of HIF-1 alpha on hepatocellular carcinoma cell apoptosis and Omit HtrA2 expression. In our study we found that HIF-1 alpha gene could suppress hepatoma cell apoptosis, and Omi/HtrA2 mRNA and protein expression decreased with HIF-1 alpha expression increase while Bcl-2 mRNA and protein expression increased with HIF-1 alpha expression increase in HepG2 cells under normoxia condition. Meanwhile, Omi/HtrA2 protein expression increased with HIF-1 alpha expression decrease in HepG2 cells under hypoxia culture. Taken together, these results demonstrated that HIF-1 alpha suppressed hepatocellular carcinoma cell apoptosis through inhibiting Omi/HtrA2 expression and upregulating Bcl-2 expression to impede Omi/HtrA2 releasing from the mitochondrion. The present finding further enriched and supported the role of HIF-1 alpha expression on cell apoptosis of hepatoma cells.