To investigate the role of adhesion molecules in C protein–induced myositis (CIM), a murine model of polymyositis (PM). CIM was induced in wild-type mice, L-selectin–deficient (L-selectin−/−) mice, intercellular adhesion molecule 1 (ICAM-1)–deficient (ICAM-1−/−) mice, and mice deficient in both L-selectin and ICAM-1 (L-selectin−/−ICAM-1−/− mice). Myositis severity, inflammatory cell infiltration, and messenger RNA expression in the inflamed muscles were analyzed. The effect of dendritic polyglycerol sulfate, a synthetic inhibitor that suppresses the function of L-selectin and endothelial P-selectin, was also examined. L-selectin−/− mice and L-selectin−/−ICAM-1−/− mice developed significantly less severe myositis compared to wild-type mice, while ICAM-1 deficiency did not inhibit the development of myositis. L-selectin−/− mice that received wild-type T cells developed myositis. Treatment with dendritic polyglycerol sulfate significantly diminished the severity of myositis in wild-type mice compared to treatment with control. These data indicate that L-selectin plays a major role in the development of CIM, whereas ICAM-1 plays a lesser role, if any, in the development of CIM. L-selectin–targeted therapy may be a candidate for the treatment of PM.