The coxsackievirus and adenovirus receptor (CAR) mediates entry of coxsackievirus and adenovirus. CAR possesses an extracellular region that is comprised of 2 immunoglobulin domains termed CAR–D1 and CAR–D2. In the present work, the solution structure of CAR–D2, consisting of residues 142–235 of human CAR, has been determined by NMR spectroscopy. CAR–D2 is shown to be a β-sandwich motif comprised of two β-sheets, which are stabilized by two disulfide bonds. The first β-sheet is comprised of β-strands A, B, and E, and the second β-sheet is comprised of β-strands C, F, and G. A relatively hydrophobic helix is found between β-strands C and E, which replaces β-strand D of the classical c-type immunoglobulin fold.