Intercellular adhesion molecule‐1 (ICAM‐1) plays an important role in leukocyte trafficking, induction of cellular immune responses, and immunological synapse formation. As a member of the immunoglobulin superfamily of adhesion proteins, ICAM‐1 is composed of repeating Ig‐like domains, a transmembrane domain, and short cytoplasmic tail that participates in intracellular signaling events. At least seven ICAM‐1 protein isoforms are generated by alternative splicing, however little is known regarding their immunobiology. We have previously shown using different lines of ICAM‐1 mutant mice (Icam1^tm1Jcgr and Icam1^tm1Bay) that expression of alternatively spliced ICAM‐1 isoforms can significantly influence the disease course during the development of EAE. In this study, we show using a newly developed transgenic mouse (CD2‐Icam1^D4del/Icam1^null) that T‐cell‐specific expression of a single ICAM‐1 isoform composed of Ig domains 1, 2, 3, and 5 can mediate the initiation and progression of EAE. Our results indicate that the ICAM‐1 isoform lacking Ig domain 4 can drive pathogenesis in demyelinating disease and may be a novel therapeutic target for treating multiple sclerosis.