The liver is normally the major site of glucose metabolism in intact organisms and the most important targetorgan for the action of insulin. It has been widely accepted that insulin resistance (IR) is closely associated withpostoperative recurrence of hepatocellular carcinoma (HCC). However, the relationship between IR and drugresistance in liver cancer cells is unclear. In the present study, IR was induced in HepG2 cells via incubationwith a high concentration of insulin. Once the insulin-resistant cell line was established, the stability of HepG2/IR cells was further tested via incubation in insulin-free medium for another 72h. Afterwards, the biologicaleffects of insulin resistance on adhesion, migration, invasion and sensitivity to cis-platinum (DDP) of cells weredetermined. The results indicated that glucose consumption was reduced in insulin-resistant cells. In addition,the expression of the insulin receptor and glucose transportor-2 was downregulated. Furthermore, HepG2/IRcells displayed markedly enhanced adhesion, migration, and invasion. Most importantly, these cells exhibited alower sensitivity to DDP. By contrast, HepG2/IR cells exhibited decreased adhesion and invasion after treatmentwith the insulin sensitizer pioglitazone hydrochloride. The results suggest that IR is closely related to drugresistance as well as adhesion, migration, and invasion in HepG2 cells. These findings may help explain theclinical observation of limited efficacy for chemotherapy on a background of IR, which promotes the invasionand migration of cancer cells.