Abstract GDP- d-mannose 4,6 dehydratase is the first enzyme in the de novo biosynthetic pathway of GDP- l-fucose, the activated form of l-fucose, a monosaccharide found in organisms ranging from bacteria to mammals. We determined the three-dimensional structure of GDP- d-mannose 4,6 dehydratase from the Paramecium bursaria Chlorella virus at 3.8 Å resolution. Unlike other viruses that use the host protein machinery to glycosylate their proteins, P. bursaria Chlorella virus modifies its structural proteins using many glycosyltransferases, being the first virus known to encode enzymes involved in sugar metabolism. P. bursaria Chlorella virus GDP- d-mannose 4,6 dehydratase belongs to the short-chain dehydrogenase/reductase protein superfamily. Accordingly, the family fold and the specific Thr, Tyr, and Lys catalytic triad are well conserved in the viral enzyme.