Cisplatin [cis-diamminedichloroplatinum (II)], is a platinum coordination compound that is commonly used to treat hepatocellular carcinoma (HCC). It is also one of the most compelling anticancer drugs. Recent studies suggest that cisplatin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of cisplatin in several types of cancers, including HCC, has not been elucidated. The goal of the present study was to evaluate the effects of cisplatin on the proliferation of HCC cells in vitro and to determine which microRNAs (miRNAs) are associated with the anticancer effects of cisplatin in vitro. We used various human HCC-derived cell lines to study the effects of cisplatin on human HCC cells. Cisplatin led to a strong dose- and time- dependent inhibition of cell proliferation in HLE, HLF, HuH7, Li-7, Hep3B and HepG2 cells in vitro. Cisplatin also blocked the progression of the cell cycle in the G0/G1 phase, which inhibited cyclin D1 and induced apoptosis. In addition, miRNA expression was markedly altered by treatment with cisplatin in vitro. Therefore, various miRNAs induced by cisplatin may also contribute to the suppression of cellular proliferation and apoptosis. Our results demonstrate that cisplatin inhibits the growth of HCC, possibly through the induction of G1 cell cycle arrest and apoptosis through the alteration of microRNA expression.