The present study investigated the possibility that acute stress might activate microglial cells. Wistar rats were exposed to 2 h period of restraint combined with water immersion stress prior to brain analysis by immunohistochemistry with OX-42, a marker of complement receptor CR3. A single session of stress provoked robust morphological microglial activation in the thalamus, hypothalamus, hippocampus, substantia nigra and central gray. These effects appeared as early as at 1 h of exposure and were further intensified at 2 h. Morphological activation was not accompanied with changes in markers of functional activation or of inflammation including interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS). Similar results were obtained with mice where the effects of stress were compared in animals null for interleukin-18 (IL-18 KO), a cytokine previously demonstrated to be modulated by stress and to contribute to microglia activation. The results demonstrated significant reduction of stress-induced microglial activation in IL-18 KO mice. The present study reports evidence that physical/emotional stress may induce morphological microglial activation in the brain and this activation is in part mediated by interleukin-18.