Although neurotransmitters and neuropeptides are known to affect immune function in vitro and in non-neural tissues, little is known about how the local mix of neurochemicals affects immune function in the brain. Here, we study local modulation of the class II major histocompatibility complex (MHC) proteins, which present antigen to T cells in a key pathway for cell-mediated immune activity. Two sites that are well-separated anatomically and have very different neuroregulatory environments, the brainstem and hippocampus, were compared. The class II-upregulating cytokine, gamma interferon (IFN-gamma, 0.1 to 10,000 U/site), was injected stereotaxically into the hippocampus and contralateral brainstem of adult Charles-derived Fischer rats. Four days later, monoclonal antibody staining was used to detect class II MHC proteins on cryostat sections, followed by computer-assisted image analysis. As compared to hippocampus, the brainstem showed enhanced class II expression at lower IFN-gamma doses, and reached a higher plateau. Site-specific class II modulation was also seen within the layers of the hippocampus, and among other brain sites. Injection of marker protein to visualize the spread of injected protein, plus injection of IFN-gamma into alternative sites, suggested that preferential flow cannot explain all of the site-specific effects. We suggest that the local neuroregulatory environment and/or intrinsic differences among target microglia are likely to play a role. Implications for the distribution of pathological changes, such as multiple sclerosis plaques, and for local immunotherapy are discussed.