Flavopiridol, as a cyclin-dependent kinase (CDK) inhibitor, has entered into phase II study of clinical trial in chronic lymphocytic leukemia. In our study, flavopiridol decreased cell viability, significantly arrested cell cycle in G1 phase and induced cell apoptosis in HepG2/ 2.2.1 cells. Flavopiridol also inhibited protein expression of cyclin D1, cyclin-dependent kinase 4 (CDK4), cyclindependent kinase 6 (CDK6), and downregulated X-linked IAP (XIAP) expression in a dose-dependent manner. Further studies using HepG2/2.2.1 cells transfected with CDK6 siRNA or expression vector demonstrated that CDK6 modulates expression of XIAP. Finally, treatment of HepG2/2.2.1 cells with combination of flavopiridol and embelin, as a XIAP specific inhibitor, could inhibit cell proliferation more effectively than each drug alone. Taking together, CDK6 regulates XIAP expression in hepatocellular carcinoma (HCC) cells. Combination of flavopiridol and embelin could be potentially used for HCC treatment subsequently.