Objective: It is becoming clear that the CNS receives signals from the peripheral immune system. In order to identify the areas of the brain that receive information about a specific immune response to allogeneic antigens, we studied the expression of c-Fos, a neural activation marker, in the cerebral cortex following the induction of a graft-vs.-host reaction (GvHR) in rats. Methods: C-Fos expression in the brain was studied by immunohistochemistry. GvHR was induced in (WKY × PVG)F<sub>1</sub> rats by injecting 5 × 10<sup>8</sup> spleen cells from PVG rats. Control rats received syngeneic cells. Results: No c-Fos immunoreactivity (IR) was observed in animals undergoing GvHR in the nucleus tractus solitarii (NTS), the locus coeruleus (LC), the organum vasculosum of lamina terminalis (OVLT), the paraventricular nucleus (PVN) or the central amygdaloid nucleus (Ce). In contrast, 3 days after GvH induction c-Fos IR was observed in the piriform cortex and several other olfactory-related regions indicating the stimulation of the olfactory pathway during GvHR. Strong c-Fos IR was also observed in the occipital visual cortex of animals undergoing a GvHR, suggesting that GvHR can affect visual functions. In addition, GvHR induced c-Fos IR in the prefrontal cortex (Cg3, orbital cortex), a region that has interconnections with most sensory modalities. Double-staining studies indicate that the cells that express the c-Fos signal are neurons. Conclusion: We have defined the distribution of brain neurons that are affected during the induction phase of GvHR. Our results also indicate that the integration and processing of information from the immune system at CNS levels involve different areas during different types of immune responses.