Recent studies from our laboratory and by other investigators have shown that autoreactive CD4+ cells specific for peripheral nerve P2 protein have a powerful effect on blood-nerve barrier permeability. In this study we injected CD4+ T cells reactive to a nonneural antigen (ovalbumin) systemically and achieved their accumulation in the tibial nerve of Lewis rats by previous intraneural injection of ovalbumin. Selected rats were given systemic demyelinating antibody (antigalactocerebroside) to provide an indicator of changes in the permeability of the blood-nerve barrier, and the animals were monitored by sequential neurophysiological studies and histology. Circulating ovalbumin-specific T cells accumulated at sites of intraneural ovalbumin injection without inducing demyelination in control animals. In rats with circulating galactocerebroside antibodies, local conduction block and demyelination were seen in the region of T-cell accumulation. Electron microscopy demonstrated dissolution of some tight junctions between endothelial cells in areas of T-cell accumulation, and T cells traversing the endothelium between endothelial cells and through their cytoplasm. Endothelial cell damage was evident in these areas. This study demonstrates breakdown of the blood-nerve barrier by activated T cells, even of nonneural specificity, allowing the development of focal conduction block and demyelination in the presence of circulating antimyelin antibodies.