Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Surgical resection and liver transplantation are still the best options for treatment. Nevertheless, as the number of patients who may benefit from these therapies is limited, alternative therapies have been developed, including chemotherapy. However, partly due to the expression of multidrug resistance (MDR) proteins, it has been found that HCC is a highly chemoresistant tumor. The major family of MDR proteins is the ATP-binding cassette (ABC) transporter superfamily, which includes P-glycoprotein (Pgp) and MDR-associated protein 1 (MRP1). Positron emission tomography using the radiolabeled analog of glucose, 2-deoxy-2-((18)F)fluoro-D-glucose ([(18)F]FDG), has been used in diagnostic imaging of various types of tumors. Clinical studies are inconsistent but experimental studies have shown that [(18)F]FDG uptake is associated with tumor grade and is inversely proportional to Pgp expression in HCC. These studies unveil that [(18)F]FDG can be a substrate of Pgp, although that relationship remains unclear. This review sums up the relationship between MDR expression in HCC, and [(18)F]FDG uptake by tumor cells, showing that this radiopharmaceutical may provide a useful tool for the study of chemoresistance in HCC, and that the use of this marker may contribute to the therapeutic choice on this highly aggressive tumor.