We present a case of acute neuroborreliosis in the setting of long-term treatment with natalizumab. A 33-year-old man was diagnosed with relapsing-remitting multiple sclerosis (MS) in 1999. Following failure of various immunomodulatory treatments including interferon and immunoglobulin, he was treated with mitoxantrone from May 2000 to August 2004. Due to persistently high disease activity, he was also treated with cyclophosphamide (December 2005-April 2006) and then azathioprine (April-June 2006), which were both discontinued due to adverse effects. After the patient scored 6.5 on the Expanded Disability Status Scale and had 2 relapses in 2006, we initiated natalizumab therapy (300 mg monthly, starting September 2006). The patient improved significantly in ambulation and the relapse rate slowed as well.