Activation of glial cells often occurs at sites of neuronal injury or death and where there is disruption of communication between glia and neurons. We have previously reported that neurons exert an inhibitory influence on LPS-stimulated nitric oxide (NO) production in glial cells. We hypothesized that neural cell adhesion molecules (NCAM) might mediate this inhibitory effect, and this study was designed to elucidate the role of NCAM on lipopolysaccharide (LPS)-induced NO production. We found that soluble NCAMs reduced LPS-stimulated NO production by cultured glia. A monoclonal antibody that recognizes the third immunoglobulin (Ig) domain and can mimic the functions of NCAMs reduced LPS-stimulated NO production, whereas another antibody that binds to other regions of the NCAM did not modulate NO production. Using a 10-amino acid peptide from the third Ig domain of the NCAM, a peptide fragment within the region recognized by the NCAM antibody, mimics the effect of the molecule in reducing NO production. This study demonstrated that NCAMs could modulate LPS-stimulated NO production, most likely via interaction between NCAMs. These results suggest that neuron-glia interactions via NCAMs play an important role in regulating the activities of glial cells in the brain.