Multiple sclerosis is characterized by the infiltration of leukocytes into the CNS. As matrix metalloproteinases (MMPs) facilitate the passage of leukocytes across matrix barriers, we tested the hypothesis that targeting MMPs could attenuate neuro-inflammation. We report that minocycline, a widely used generic drug with a good safety record, inhibited MMP activity, reduced production of MMP-9 and decreased the transmigration of T lymphocytes across a fibronectin matrix barrier. In addition, minocycline was efficacious against both mild and severe experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis. When severe EAE was produced, minocycline pre-treatment delayed the course of the disease: when maximal disease activity occurred in vehicle-treated EAE mice, minocycline animals were relatively normal and had minimal signs of inflammation and demyelination in the CNS. When tested in mice afflicted with mild EAE, minocycline attenuated the clinical severity of disease throughout the course of treatment. These results indicate that minocycline may constitute a safe and inexpensive therapy for multiple sclerosis.