Multiple sclerosis (MS) is an inflammatory neurological disorder associated with demyelination, impaired blood brain barrier (BBB), axonal damage and neuronal loss. In the present study, we measured somatostatin (SST) and tumor necrosis factor-α (TNF-α) like immunoreactivity in CSF samples from MS and non-MS patients. We also examined the role of SST in cytokines and lipopolysaccharide (LPS)-induced damage to the BBB using human brain endothelial cells in culture. Most of the cerebrospinal fluid (CSF) samples studied from definite MS patients exhibited lower somatostatin (SST)-like immunoreactivity and higher expression of TNF-α in comparison to non-MS patients. Treatment of cells with cytokines and LPS blocked SST secretion and decreased SST expression. Human brain endothelial cells expressed all five somatostatin receptors (SSTRs) with increased expression of SSTR2 and 4 upon treatment with cytokines and LPS. Cytokines and LPS-induced disruption of the tight junction proteins Zonula occludens (ZO-1) organization was restored in presence of SST, SSTR2 or SSTR4 selective agonists. Furthermore, inflammation induced changes in extracellular signal-regulated kinases (ERK1/2 and ERK5) signaling and altered expression of endothelial and inducible nitric oxide synthase are modulated in presence of SST. These data indicate that decreased levels of SST contribute to failure of the BBB in MS.