To determine whether hepatocyte membrane potential differences (PDs) are depolarized in human HCC and whether depolarization is associated with changes in GABA A receptor expression, hepatocyte PDs and ␥-aminobutyric acid (GABA) A receptor messenger RNA (mRNA) and protein expression were documented in HCC tissues via microelectrode impalement, real-time reverse-transcriptase polymerase chain reaction, and Western blot analysis, respectively. HCC tissues were significantly depolarized (؊19.8 ؎ 1.3 versus ؊25. In recent in vitro studies, we demonstrated that restoration of depolarized malignant hepatocyte cell membrane potential differences (PDs) toward those documented in nonmalignant hepatocytes results in a loss of malignant features, including decreased proliferative activity, absence of colony formation in soft agar, and normalization of phenotypic appearance. 2 Whether HCC tissues are depolarized relative to adjacent nontumor tissues and the mechanisms whereby such depolarization might exist have yet to be reported.