Anti-tumor necrosis factor-α (TNF) agents have dramatically changed the management of Crohn’s Disease (CD). However, a significant number of these patients do not respond at all or cease to respond to antibodies against TNF. In this clinical situation, the options include intensification of anti-TNF therapy by either increasing the dose or by shortening the administration interval, the use of a second anti-TNF or medications with a different mechanism of action. Among the later, Natalizumab, a humanized IgG4 monoclonal antibody against α4β1 and α4β7 integrins, is safe and effective in inducing and maintaining remission in active CD patient’s refractory to anti-TNF. In spite of this, Natalizumab use has been limited because of an increased risk of progressive multifocal leukoencephalophaty which results from reactivation of the John Cunningham (JC) virus. However, the presence of antibodies against JC virus in serum can be used to reduce the risk for this complication. We report three patients with Crohn’s disease refractory to treatment with infliximab, who responded successfully to the use of Natalizumab.