Introduction: Apoptosis resistance in Hepatocellular Carcinoma (HCC) is considered as one of the most important factors inv- olved in hepatocarcinogenesis and its progression. Recent experimental research of melatonin highlights its anticancer function through its antioxidant effect, induction of apoptosis and cell cycle arrest, inhibition of metastasis, and suppression of angiogenesis. The aim of our study is to explore the effect of melatonin on casp 8 mRNA expression and Alpha-fetoprotein (AFP) mRNA expression in HepG2 HCC cell line by using real time PCR technique to proof its apoptotic effect. Methods: HepG2 cells were treated with 75mg melatonin then AFP mRNA expression and casp8 expression is investigated by RT PCR. Results: Melatonin significantly increased caspase 8 expression. The relative expression was 2.51, 2.48 and1.89 respectively as com- pared to control (P