Two human esophageal cancer cell lines (KYSE-510 and OE33) were chosen as the tumor model to explore molecular mechanism of flavones and flavonols on induction of apoptosis. Effects of flavones (luteolin, apigenin, chrysin) and flavonols (quercetin, kaempferol, myricetin) on induction of apoptosis in KYSE-510 cells and OE33 cells were observed by DNA fragmentation, acridine orange staining and flow cytometry analysis. The results of real-time RT-PCR and Western-blot analysis showed that the treatment of KYSE-510 cells and OE33 cells with flavones and flavonols induced the expression of PIG3 at the mRNA and the protein levels. Western-blot analytical results further showed that induction of PIG3 caused apoptosis in both esophageal cancer cells through the mitochondrial pathway in a p53-independent manner, and p63 and p73 may be responsible for the induction of PIG3.