In the central nervous system (CNS), vesicular monoamine transporter 2 (VMAT2) transports cytoplasmic monoamines such as dopamine into synaptic vesicles for storage and subsequent exocytotic release. Recent studies have provided direct evidence for VMAT2-regulated monoamine neurotransmitter involvement in the neurophysiological activities of neurological disease. This study investigated the expression pattern of VMAT2 in patients with temporal lobe epilepsy (TLE) and in a rat model of epilepsy. We assessed the expression of VMAT2 in the temporal neocortex in 24 TLE patients using western blotting and quantitative real time PCR (qRT-PCR) analyses. These results showed that VMAT2 expression dynamically decreased in TLE patients when compared with the control subjects (n = 12). And that VMAT2 protein transiently increased in acute stages (1 day and 3 days) after epileptic seizures in pilocarpine-treated rats; however, it clearly decreased after spontaneous recurrent seizures (7 days, 21 days, and 60 days after seizures). In addition, double immunofluorescence and immunohistochemical labeling studies performed in patient and experimental animal tissue revealed that VMAT2 protein was mainly expressed in the cytoplasm and in the axons of neurons but not glial cells in the hippocampus and temporal lobe cortex. These data suggested that the abnormal expression of VMAT2 mRNA and protein in epileptic brain tissue may contribute to vulnerability toward epilepsy-related psychiatric disorders and cognitive impairment. Synapse 67:415–426, 2013. © 2013 Wiley Periodicals, Inc.