Perisynaptic astroglia are critical for normal synaptic development and function. Little is known, however, about perisynaptic astroglia in the human hippocampus. When mesial temporal lobe epilepsy (MTLE) is refractory to medication, surgical removal is required for seizure quiescence. To investigate perisynaptic astroglia in human hippocampus, we recovered slices for several hours in vitro from three surgical specimens and then quickly fixed them to achieve high-quality ultrastructure. Histological samples from each case were found to have mesial temporal sclerosis with Blumcke Type 1a (mild, moderate) or 1b (severe) pathology. Quantitative analysis through serial section transmission electron microscopy in CA1 stratum radiatum revealed more synapses in the mild (10/10 microm(3)) than the moderate (5/10 microm(3)) or severe (1/10 microm(3)) cases. Normal spines occurred in mild and moderate cases, but a few multisynaptic spines were all that remained in the severe case. Like adult rat hippocampus, perisynaptic astroglial processes were preferentially associated with larger synapses in the mild and moderate cases, but rarely penetrated the cluster of axonal boutons surrounding multisynaptic spines. Synapse perimeters were only partially surrounded by astroglial processes such that all synapses had some access to substances in the extracellular space, similar to adult rat hippocampus. Junctions between astroglial processes were observed more frequently in moderate than mild case, but were obscured by densely packed intermediate filaments in astroglial processes of the severe case. These findings suggest that perisynaptic astroglial processes associate with synapses in human hippocampus in a manner similar to model systems and are disrupted by severe MTLE pathology.