In Multiple Sclerosis (MS) pathology, early inflammation involves leukocyte migration across the blood-brain barrier (BBB) within the central nervous system. In this process, adhesion molecules (AMs), both membrane-bound and soluble-circulating forms, and matrix metalloproteinases (MMPs) certainly play a regulatory role. In MS, recombinant Interferon-beta (rIFNbeta) is effective in reducing gadolinium contrast-enhancing lesions on magnetic resonance imaging and this suggests that it may reduce BBB damage or even restore its integrity by different mechanisms that include interference with both AM and MMP pathways. This review will highlight the effects induced by rIFNbeta, both in vitro and in vivo, on cell-bound and soluble forms of AMs and on MMPs.