Rationale: Astroglial cells (astrocytes), previously considered mere support cells in the central nervous system, are now understood to be key players in integrating neuronal inputs and modulating synaptic density. Astrocytic processes surround the perikaryons and neuronal processes including dendritic spines and by extension or retraction, respectively, lyse or facilitate increases in number or size of synapses. Astrocytes express estrogen receptors and in animal models, including monkeys, have been shown to respond to estradiol by changing the disposition of their processes in a manner opposite to the number of synapses. Experimental: Our objective was to examine the effects of estradiol and two other clinically available Selective Estrogen Receptor Modulators (SERMs; tamoxifen and raloxifene) on astrocyte processes in human brain tissue. To accomplish this goal, we used simultaneous immunostaining of the glial cytoskeletal marker glial acidic protein (GFAP) and ezrin, a membrane-cytoskeletal linker, plus light microscopy image analysis to study the thinness and branching of randomly selected human temporal lobe neocortical astrocytes after a 60-minute incubation of 400µ temporal lobe slices. Effects of estradiol (10 nM), raloxifene and tamoxifen (1.0 µM) were compared with untreated control slices. Results: Changes were confirmed in the branchings of temporal lobe astrocytes during the 60-minute incubation period. Astrocytes in control slices extended their branches and became thinner. Parallel changes were present in tamoxifen-cultured slices. Raloxifene-treated slices showed significant reduction of astrocyte branching and thinning compared to controls (p = 0.01, 0.01, 0.06 for primary, secondary, and tertiary processes, respectively). An intermediate reduction of astroglial process size was present following estradiol treatment, but not at a statistically significant level compared to controls. Conclusions: These preliminary results support estrogen receptor modulator regulation of human astroglial processes in a manner consistent with previous reports on animals in which changes in glial spreading plays a role in synaptic changes. Neuroendocrinological implications are discussed.