Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenous infusion. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier.^{[medical citation needed]}

Natalizumab is a monoclonal antibody which targets a protein called α4β1 integrin on white blood cells involved in inflammation. By attaching to integrin, natalizumab is thought to stop white blood cells from entering the brain and spinal cord tissue, thereby reducing inflammation and the resulting nerve damage.

The most common side effects are urinary tract infection, nasopharyngitis (inflammation of the nose and throat), headache, dizziness, nausea, joint pain and tiredness.

Natalizumab was approved for medical use in the United States in 2004. It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy (PML) when administered in combination with interferon beta-1a, another immunosuppressive drug often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the European Medicines Agency. By 2010, 31 cases of PML were attributed to natalizumab while by 2018 this had risen to 757 cases. The US Food and Drug Administration (FDA) did not withdraw the drug from the market as benefits outweigh the risks. In the European Union, it has been approved only for multiple sclerosis and only by itself as the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the person.

In the United states, natalizumab is indicated for the treatment of multiple sclerosis and Crohn's disease. It is indicated to treat clinically isolated syndrome (a single, first occurrence of multiple sclerosis symptoms); relapsing-remitting disease (a fluctuation between episodes of new neurological symptoms followed by periods of stability) and active secondary progressive disease (gradual disability worsening with continued relapses following a relapsing-remitting course).

Natalizumab offers a limited improvement in efficacy compared to other treatments for multiple sclerosis, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications. Natalizumab is used as a monotherapy.

In the European Union, natalizumab is indicated as single disease modifying therapy in adults with highly active relapsing remitting multiple sclerosis for the following patient groups:

The US prescribing information for natalizumab contains a boxed warning about the increased risk of progressive multifocal leukoencephalopathy, a viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of progressive multifocal leukoencephalopathy include the presence of anti-JCV antibodies (antibodies to the JC virus, a typically harmless virus carried by most humans), longer duration of therapy and prior use of immunosuppressants.