Coxsackievirus B4 (CBV4), a member of the Picornavirus genus, has long been implicated in the development of insulin-dependent diabetes mellitus (IDDM), by viral-induced pancreatic cell damage. Although the pancreotropic nature of this virus is well documented, the early stages of CBV4 viral infection that involve the attachment of virions to the cell surface by binding to their cellular receptors followed by entry into the cell, are poorly understood. In this study, we show that the entry of CBV4 requires functional lipid rafts as the site of virus attack. In addition, we show that this virus is endocytosed independently of clathrin-associated machinery and is delivered to the Golgi via a lipid-raft-dependent mechanism.